TWI674898B - Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof - Google Patents

Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof Download PDF

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TWI674898B
TWI674898B TW107100489A TW107100489A TWI674898B TW I674898 B TWI674898 B TW I674898B TW 107100489 A TW107100489 A TW 107100489A TW 107100489 A TW107100489 A TW 107100489A TW I674898 B TWI674898 B TW I674898B
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TW201828942A (en
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戴爾 波特
安薩 哈利洛維奇
瑪雅 泉琳恩
安娜 萊蒂西亞 莫雷葛諾
奧莉薇 居內斯特
戴爾芬妮 密利諾
詹姆士 懷特雷
法蘭寇斯 拜蘭特
珍妮 畢司巴德
吉歐弗瑞 林德曼
古優勞密 雷森尼
艾莉莎貝塔 馬藍果尼
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法商施維雅藥廠
瑞士商諾華公司
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Abstract

本發明係關於一種包含MCL-1抑制劑及紫杉烷化合物之組合及其組合物及用途。The present invention relates to a combination comprising an MCL-1 inhibitor and a taxane compound, and a composition and use thereof.

Description

MCL-1抑制劑及紫杉烷化合物之組合，及其用途及醫藥組合物Combination of MCL-1 inhibitor and taxane compound, use thereof and pharmaceutical composition

本發明係關於一種MCL-1抑制劑與紫杉烷化合物之組合。本發明亦關於該組合在癌症治療，尤其乳癌、肺癌、卵巢癌、膀胱癌及前列腺癌，更特定而言乳癌及肺癌治療中之用途。亦提供適用於施行此類組合之醫藥調配物。The present invention relates to a combination of an MCL-1 inhibitor and a taxane compound. The invention also relates to the use of the combination in the treatment of cancer, especially breast cancer, lung cancer, ovarian cancer, bladder cancer and prostate cancer, and more specifically in the treatment of breast cancer and lung cancer. Pharmaceutical formulations suitable for performing such combinations are also provided.

癌症之特徵為不受控細胞增殖。由於其對細胞分裂之重要影響，已探索抗有絲分裂劑及抗微管劑用於癌症療法。對有絲分裂機構之抑制引起一系列不同的結果，主要導致細胞週期停滯及細胞死亡。抗微管劑，諸如紫杉烷目前正用於臨床配置中。舉例來說，太平洋紫杉醇(paclitaxel)及多西他賽(docetaxel)具有相似範圍之臨床活性，包括卵巢癌、肺癌、乳癌、膀胱癌及前列腺癌。紫杉烷係抗有絲分裂劑，其結合於微管蛋白且抑制微管解聚合從而干擾參與微管組裝及解構正常平衡且因此損害微管功能。微管係細胞分裂所必需的，且暴露於紫杉烷之細胞會無法分化。使用紫杉烷治療後之細胞週期停滯會因有絲分裂失敗而最終導致細胞死亡。儘管抗癌療法之發展，一直需要毒性有限的更有效的療法。實際上，與太平洋紫杉醇及多西他賽相關聯之毒性包括嗜中性球減少症作為主要劑量限制毒性，以及顯著周邊神經病變。事實上，在經大量預治療之患者中經常減少劑量以減輕此等毒性之嚴重度。在此之上，對紫杉烷之抗性之發展亦極限其在臨床上之使用。 細胞凋亡係由各種細胞毒性刺激，包括致癌壓力及化學治療劑啟動之高度調節的細胞死亡路徑。已表明，逃避細胞凋亡係癌症之標誌且多種化學治療劑之功效依賴於固有粒線體路徑之活化。BCL-2家族蛋白之三個相異子組控制固有細胞凋亡路徑：(i)促凋亡BH3 (Bcl-2同源3)-僅蛋白；(ii)促存活成員，諸如BCL-2本身、BCL-xL、BCL-W、MCL-1及BCL-2A1；及(iii)促凋亡效應蛋白BAX及BAK (Czabotar等人，Nature Reviews Molecular Cell Biology 2014, 15, 49-63)。在許多癌症中觀測到BCL-2家族之抗凋亡成員之過度表現(Adams and Cory,Oncogene 2007, 26, 1324-1337)，且已出現藉由BH3-模擬物藥物，諸如ABT-199 (維托拉斯(venetoclax))、ABT-263 (納維克拉斯(navitoclax))及S63845之抗凋亡蛋白之藥理學抑制作為治療性策略以誘發細胞凋亡且引起癌症之腫瘤消退(Zhang等人，Drug Resist . Updat . 2007, 10, 207-217；Kotschy等人，Nature 2016, 538, 477-482)。儘管如此，已觀測到對BH3模擬物之抗性機制(Choudhary等人，Cell Death and Disease 2015, 6, e1593)且使用組合療法可以提高功效且延遲或甚至消除抗性之發展。 乳癌係異質疾病且可基於基因表現特徵分為至少五個主要子組：魯米那(Luminal) A型、魯米那B型(雌激素正，ER+ )、HER2擴增的、基底樣(主要為三陰性乳癌或TNBC)及正常樣(Curtis等人，Nature 2012, 486, 346-352; Perou等人，Nature 2000, 406, 747-752)。此等子類型通常預測關於對療法之反應及抗性轉移之模式及總存活率的臨床特性。多個機製造成腫瘤進展及對癌症療法之抗性，包括由於BCL2家族之抗凋亡成員及促凋亡成員之間之平衡失調引起之逃避細胞死亡(Merino等人，Oncogene 2016, 35, 1877-1887；Beroukim等人，Nature 2010, 463, 899-905；Wertz等人，Nature 2011, 471, 110-114；Goodwin等人，Cell Death Differ . 2015)。在三陰性乳癌子組中，相比於達到病理性完全反應之患者，在新佐劑療法之後殘餘疾病與更高風險之轉移性復發相關聯(Liedtke等人，J . Clin . Oncol . 2008, 26(8), 1275-1281)。約70%之TNBC患者在新佐劑化學療法(諸如太平洋紫杉醇或多西他賽)之後不達到完全反應且遭受顯著更壞的結果，轉移性復發之概率更高且3年總存活率僅60%至70%。 肺癌分為非小細胞肺癌(non-small cell lung cancer，NSCLC)、小細胞肺癌(small cell lung cancer，SCLC)及類癌。所有肺癌中大約80%與NSCLC對應，其可以進一步分為腺癌、鱗狀細胞癌及大細胞癌。肺癌係男性之癌症相關死亡之最常見原因，且係繼乳癌之後，女性之癌症相關死亡之第二常見原因。雖然隨著靶向療法之出現肺癌療法已顯著進化，但仍強烈地需要發展新穎療法以提高治療功效、降低副作用且避免抗性之出現(RothschildCancers 2015, 7(2), 930-949)。 本發明提供一種MCL-1抑制劑與紫杉烷化合物之新穎組合。結果顯示，靶向MCL-1之強力小分子與抗微管劑之關聯在乳癌及肺癌細胞株中高度協同(圖1至圖7；表1及表4)。吾人亦展示，在乳癌PDX (患者衍生異種移植物)模型中在容許劑量下(圖8及圖9)及在攜帶MDA-MB-231異種移植物(一種三陰性乳癌模型)之雌性裸大鼠中在不同劑量下(圖10至圖14)活體內經組合的干擾微管功能及MCL-1靶向係有效的。使用不同投藥方案，亦在TNBC之不同PDX模型中觀測到積極組合(圖15)。已經由強力小分子抑制劑之組合顯示出在容許劑量下活體外及活體內靶向MCL-1與干擾微管功能之協同作用。最後，為研究化學抗性，新佐劑治療之後之殘餘腫瘤分析係主要且正在探索的領域，且因此，吾人在對化學療法有抗性之PDX模型中進行實驗，顯示MCL-1抑制劑與紫杉烷化合物之組合係有效的(實例9)。Cancer is characterized by uncontrolled cell proliferation. Due to their important effect on cell division, antimitotic and antimicrotubule agents have been explored for use in cancer therapy. Inhibition of mitotic mechanisms causes a series of different results, mainly leading to cell cycle arrest and cell death. Anti-microtubule agents such as taxanes are currently being used in clinical settings. For example, paclitaxel and docetaxel have similar ranges of clinical activity, including ovarian, lung, breast, bladder, and prostate cancer. Taxane-based antimitotic agents bind to tubulin and inhibit microtubule depolymerization, thereby interfering with the normal balance of microtubule assembly and destructuring and thus impairing microtubule function. Microtubule system cells are necessary for cell division, and cells exposed to taxanes cannot differentiate. Cell cycle arrest after taxane treatment will eventually lead to cell death due to mitotic failure. Despite the development of anticancer therapies, there is a continuing need for more effective therapies with limited toxicity. In fact, the toxicity associated with paclitaxel and docetaxel includes neutropenia as the main dose-limiting toxicity, and significant peripheral neuropathy. In fact, doses are often reduced in patients who have undergone extensive pretreatment to reduce the severity of such toxicity. On top of this, the development of resistance to taxanes has also limited their clinical use. Apoptosis is a highly regulated cell death pathway stimulated by a variety of cytotoxicities, including carcinogenic stress and chemotherapeutic agents. It has been shown that escape from apoptosis is a hallmark of cancer and that the efficacy of various chemotherapeutic agents depends on the activation of the intrinsic mitochondrial pathway. Three distinct subgroups of BCL-2 family proteins control the intrinsic apoptotic pathway: (i) pro-apoptotic BH3 (Bcl-2 homology 3) -only protein; and (ii) pro-survival members such as BCL-2 itself , BCL-xL, BCL-W, MCL-1 and BCL-2A1; and (iii) pro-apoptotic effectors BAX and BAK (Czabotar et al., Nature Reviews Molecular Cell Biology 2014, 15, 49-63). Excessive expression of anti-apoptotic members of the BCL-2 family has been observed in many cancers (Adams and Cory, Oncogene 2007, 26, 1324-1337), and has emerged through the use of BH3-mimetic drugs such as ABT-199 (dimensional Venetoclax), ABT-263 (navitoclax), and pharmacological inhibition of anti-apoptotic proteins of S63845 as therapeutic strategies to induce apoptosis and cause cancer regression (Zhang et al., Drug Resist . Updat . 2007, 10, 207-217; Kotschy et al., Nature 2016, 538, 477-482). Nevertheless, resistance mechanisms to BH3 mimics have been observed (Choudhary et al., Cell Death and Disease 2015, 6, e1593) and the use of combination therapies can increase efficacy and delay or even eliminate the development of resistance. Breast cancer is a heterogeneous disease and can be divided into at least five major subgroups based on gene expression characteristics: Luminal A, Lumina B (estrogen positive, ER + ), HER2 amplified, basal-like ( Mainly triple negative breast cancer or TNBC) and normal (Curtis et al., Nature 2012, 486, 346-352; Perou et al., Nature 2000, 406, 747-752). These subtypes often predict clinical characteristics regarding patterns of response to therapy and resistance transfer, and overall survival. Multiple mechanisms contribute to tumor progression and resistance to cancer therapies, including escape from cell death due to imbalance between the anti-apoptotic and pro-apoptotic members of the BCL2 family (Merino et al., Oncogene 2016, 35, 1877- 1887; Beroukim et al., Nature 2010, 463, 899-905; Wertz et al., Nature 2011, 471, 110-114; Goodwin et al., Cell Death Differ . 2015). In triple negative breast cancer subgroups, compared to patients achieve complete reaction of the pathologic, and the residue metastatic disease associated with increased risk of relapse (Liedtke, et al., After the new adjuvant therapies, J. Clin. Oncol. 2008 , 26 (8), 1275-1281). Approximately 70% of TNBC patients do not reach a complete response and experience significantly worse outcomes after neoadjuvant chemotherapy (such as paclitaxel or docetaxel), with a higher probability of metastatic relapse and a 3-year overall survival rate of only 60 % To 70%. Lung cancer is divided into non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and carcinoid. About 80% of all lung cancers correspond to NSCLC, which can be further divided into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Lung cancer is the most common cause of cancer-related deaths in men and the second most common cause of cancer-related deaths in women after breast cancer. Although lung cancer therapies have evolved significantly with the advent of targeted therapies, there remains a strong need to develop novel therapies to improve the efficacy of treatments, reduce side effects, and avoid the emergence of resistance (Rothschild Cancers 2015, 7 (2), 930-949). The present invention provides a novel combination of an MCL-1 inhibitor and a taxane compound. The results show that the association of powerful small molecules targeting MCL-1 with anti-microtubule agents is highly synergistic in breast and lung cancer cell lines (Figures 1 to 7; Tables 1 and 4). We also show that in nude breast cancer PDX (patient-derived xenograft) models at allowable doses (Figures 8 and 9) and in female nude rats carrying MDA-MB-231 xenografts (a triple-negative breast cancer model) At different doses (Figures 10 to 14), the combined in vivo microtubule function and MCL-1 targeting system are effective. Using different dosing regimens, positive combinations have also been observed in different PDX models of TNBC (Figure 15). The combination of targeting MCL-1 and interfering with microtubule function in vitro and in vivo has been shown by a combination of potent small molecule inhibitors. Finally, in order to study chemoresistance, residual tumor analysis after new adjuvant therapy is a major and under-explored field, and therefore, my experiments in a PDX model that is resistant to chemotherapy show that MCL-1 inhibitors and The combination of taxane compounds was effective (Example 9).

本發明係關於一種組合，其包含： (a)式(I)之MCL-1抑制劑：其中： ¨ D表示環烷基、雜環烷基、芳基或雜芳基， ¨ E表示呋喃基、噻吩基或吡咯基環， ¨ X1 、X3 、X4 及X5 彼此獨立地表示碳原子或氮原子， ¨ X2 表示C-R26 基團或氮原子， ¨意指環為芳族的， ¨ Y表示氮原子或C-R3 基團， ¨ Z表示氮原子或C-R4 基團， ¨ R1 表示鹵素原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、羥基(C1 -C6 )烷基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-Cy8 、-烷基(C0 -C6 )-NR11 R11 '、-O-烷基(C1 -C6 )-NR11 R11 '、 -O-烷基(C1 -C6 )-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 '、 -NR11 -C(O)-R11 '、-NR11 -C(O)-OR11 '、-烷基(C1 -C6 )-NR11 -C(O)-R11 '、 -SO2 -NR11 R11 '或-SO2 -烷基(C1 -C6 )， ¨ R2 、R3 、R4 及R5 彼此獨立地表示氫原子、鹵素原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、羥基(C1 -C6 )烷基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-烷基(C0 -C6 )-NR11 R11 '、 -O-Cy1 、-烷基(C0 -C6 )-Cy1 、-烯基(C2 -C6 )-Cy1 、-炔基(C1 -C6 )-Cy1 、-O-炔基(C1 -C6 )-NR11 R11 '、-O-烷基(C1 -C6 )-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 '、-NR11 -C(O)-R11 '、-NR11 -C(O)-OR11 '、-烷基(C1 -C6 )-NR11 -C(O)-R11 '、-SO2 -NR11 R11 '或-SO2 -烷基(C1 -C6 )， 或(R1 ，R2 )、(R2 ，R3 )、(R3 ，R4 )、(R4 ，R5 )成對取代基與攜載其的碳原子一起形成由5至7個環成員組成之芳族或非芳族環，其可含有1至3個選自氧、硫及氮的雜原子，應理解，所得環可經1至2個選自以下之基團取代：鹵素、直鏈或分支鏈(C1 -C6 )烷基、-烷基(C0 -C6 )-NR11 R11 '、 -NR13 R13 '、-烷基(C0 -C6 )-Cy1 或側氧基， ¨ R6 及R7 彼此獨立地表示氫原子、鹵素原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-烷基(C0 -C6 )-NR11 R11 '、-O-烷基(C1 -C6 )-NR11 R11 '、 -O-Cy1 、-烷基(C0 -C6 )-Cy1 、-烯基(C2 -C6 )-Cy1 、-炔基(C2 -C6 )-Cy1 、-O-烷基(C1 -C6 )-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 '、-NR11 -C(O)-R11 '、-NR11 -C(O)-OR11 '、-烷基(C1 -C6 )-NR11 -C(O)-R11 '、-SO2 -NR11 R11 '或-SO2 -烷基(C1 -C6 )， 或(R6 ，R7 )成對取代基，當接枝於兩個相鄰碳原子上時，與攜載其的碳原子一起形成由5至7個環成員組成之芳族或非芳族環，其可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可經選自以下之基團取代：直鏈或分支鏈(C1 -C6 )烷基、-NR13 R13 '、-烷基(C0 -C6 )-Cy1 或側氧基， ¨ W表示-CH2 -基團、-NH-基團或氧原子， ¨ R8 表示氫原子、直鏈或分支鏈(C1 -C8 )烷基、-CHRa Rb 基團、芳基、雜芳基、芳基烷基(C1 -C6 )基團或雜芳基烷基(C1 -C6 )基團， ¨ R9 表示氫原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、-Cy2 、-烷基(C1 -C6 )-Cy2 、-烯基(C2 -C6 )-Cy2 、-炔基(C2 -C6 )-Cy2 、-Cy2 -Cy3 、-炔基(C2 -C6 )-O-Cy2 、-Cy2 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy3 、鹵素原子、氰基、-C(O)-R14 或-C(O)-NR14 R14 '， ¨ R10 表示氫原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、芳基烷基(C1 -C6 )基團、環烷基烷基(C1 -C6 )基團、直鏈或分支鏈(C1 -C6 )多鹵烷基或-烷基(C1 -C6 )-O-Cy4 ， 或(R9 ，R10 )成對取代基，當接枝於兩個相鄰碳原子上時，與攜載其的碳原子一起形成由5至7個環成員組成之芳族或非芳族環，其可含有1至3個選自氧、硫及氮之雜原子， ¨ R11 及R11 '彼此獨立地表示氫原子、視情況經取代之直鏈或分支鏈(C1 -C6 )烷基或-烷基(C0 -C6 )-Cy1 ， 或(R11 ，R11 ')成對取代基與攜載其的氮原子一起形成由5至7個環成員組成之芳族或非芳族環，除該氮原子以外其可含有1至3個選自氧、硫及氮之雜原子，應理解所討論的氮可經1至2個表示氫原子或直鏈或分支鏈(C1 -C6 )烷基之基團取代，且應理解可能的取代基之一或多個碳原子可經氘化， ¨ R12 表示-Cy5 、-Cy5 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy6 、-Cy5 -烷基(C0 -C6 )-Cy6 、-Cy5 -烷基(C0 -C6 )-NR11 -烷基(C0 -C6 )-Cy6 、-Cy5 -Cy6 -O-烷基(C0 -C6 )-Cy7 、-Cy5 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy9 、-Cy5 -烷基(C0 -C6 )-Cy9 、-NH-C(O)-NH-R11 、-Cy5 -烷基(C0 -C6 )-NR11 -烷基(C0 -C6 )-Cy9 、 -C(O)-NR11 R11 '、-NR11 R11 '、-OR11 、-NR11 -C(O)-R11 '、-O-烷基(C1 -C6 )-OR11 、-SO2 -R11 、-C(O)-OR11 、、或， ¨ 如此定義之銨有可能以兩性離子之形式存在或具有單價陰離子相對離子， ¨ R13 、R13 '、R14 及R14 '彼此獨立地表示氫原子或視情況經取代之直鏈或分支鏈(C1 -C6 )烷基， ¨ Ra 表示氫原子或直鏈或分支鏈(C1 -C6 )烷基， ¨ Rb 表示-O-C(O)-O-Rc 基團、-O-C(O)-NRc Rc '基團或-O-P(O)(ORc )2 基團， ¨ Rc 及Rc '彼此獨立地表示氫原子、直鏈或分支鏈(C1 -C8 )烷基、環烷基、(C1 -C6 )烷氧基(C1 -C6 )烷基、或(C1 -C6 )烷氧基羰基(C1 -C6 )烷基， 或(Rc ，Rc ')成對取代基與攜載其的氮原子一起形成由5至7個環成員組成之非芳族環，其除氮原子以外可含有1至3個選自氧及氮之雜原子，應理解，所討論之氮可經表示直鏈或分支鏈(C1 -C6 )烷基之基團取代， ¨ Cy1 、Cy2 、Cy3 、Cy4 、Cy5 、Cy6 、Cy7 、Cy8 及Cy10 彼此獨立地表示環烷基、雜環烷基、芳基或雜芳基， ¨ Cy9 表示， 或Cy9 表示經選自以下之基團取代之雜芳基：-O-P(O)(OR20 )2 ；-O-P(O)(O- M+ )2 ；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 ；羥基；羥基(C1 -C6 )烷基；-(CH2 )r -U-(CH2 )s -雜環烷基；或-U-(CH2 )q -NR21 R21 '， ¨ R15 表示氫原子；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；直鏈或分支鏈(C1 -C6 )烷氧基(C1 -C6 )烷基；-U-(CH2 )q -NR21 R21 '基團；或-(CH2 )r -U-(CH2 )s -雜環烷基， ¨ R16 表示氫原子；羥基；羥基(C1 -C6 )烷基；-(CH2 )r -U-(CH2 )s -雜環烷基；(CH2 )r -U-V-O-P(O)(OR20 )2 基團；-O-P(O)(O- M+ )2 基團；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；-(CH2 )p -O-C(O)-NR22 R23 基團；或-U-(CH2 )q -NR21 R21 '基團， ¨ R17 表示氫原子；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；-O-P(O)(OR20 )2 基團；-O-P(O)(O- M+ )2 基團；羥基；羥基(C1 -C6 )烷基； -(CH2 )r -U-(CH2 )s -雜環烷基；-U-(CH2 )q -NR21 R21 '基團；或醛糖酸， ¨ M+ 表示醫藥學上可接受之單價陽離子， ¨ U表示鍵或氧原子， ¨ V表示-(CH2 )s -基團或-C(O)-基團， ¨ R18 表示氫原子或(C1 -C6 )烷氧基(C1 -C6 )烷基， ¨ R19 表示氫原子或羥基(C1 -C6 )烷基， ¨ R20 表示氫原子或直鏈或分支鏈(C1 -C6 )烷基， ¨ R21 及R21 '彼此獨立地表示氫原子、直鏈或分支鏈(C1 -C6 )烷基或羥基(C1 -C6 )烷基， 或(R21 ，R21 ')成對取代基與攜載其的氮原子一起形成由5至7個環成員組成之芳族或非芳族環，其中除該氮原子以外可再含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可經表示氫原子或直鏈或分支鏈(C1 -C6 )烷基之基團取代， ¨ R22 表示(C1 -C6 )烷氧基(C1 -C6 )烷基、-(CH2 )p -NR24 R24 '基團或 -(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團， ¨ R23 表示氫原子或(C1 -C6 )烷氧基(C1 -C6 )烷基， 或(R22 ，R23 )成對取代基與攜載其的氮原子一起形成由5至18個環成員組成之芳族或非芳族環，其除氮原子以外可含有1至5個選自氧、硫及氮之雜原子，應理解，所得環可經表示氫原子、直鏈或分支鏈(C1 -C6 )烷基或雜環烷基之基團取代， ¨ R24 及R24 '彼此獨立地表示氫原子或直鏈或分支鏈(C1 -C6 )烷基， 或(R24 ，R24 ')成對取代基與攜載其的氮原子一起形成由5至7個環成員組成之芳族或非芳族環，其中除該氮原子以外可再含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可經表示氫原子或直鏈或分支鏈(C1 -C6 )烷基之基團取代， ¨ R25 表示氫原子、羥基或羥基(C1 -C6 )烷基， ¨ R26 表示氫原子、鹵素原子、直鏈或分支鏈(C1 -C6 )烷基或氰基， ¨ R27 表示氫原子或直鏈或分支鏈(C1 -C6 )烷基， ¨ R28 表示-O-P(O)(O- )(O- )基團、-O-P(O)(O- )(OR30 )基團、-O-P(O)(OR30 )(OR30 ')基團、-O-SO2 -O- 基團、-O-SO2 -OR30 基團、-Cy10 、 -O-C(O)-R29 基團、-O-C(O)-OR29 基團或-O-C(O)-NR29 R29 '基團； ¨ R29 及R29 '彼此獨立地表示氫原子、直鏈或分支鏈(C1 -C6 )烷基或直鏈或分支鏈胺基(C1 -C6 )烷基， ¨ R30 及R30 '彼此獨立地表示氫原子、直鏈或分支鏈(C1 -C6 )烷基或芳基烷基(C1 -C6 )基團， ¨ n為等於0或1之整數， ¨ p為等於0、1或2之整數， ¨ q為等於1、2、3或4之整數， ¨ r及s獨立地為等於0或1之整數， 應理解： - 「芳基」意指苯基、萘基、聯苯基、茚滿基或茚基， - 「雜芳基」意指任何由5至10個環成員組成之單環或雙環基團，其具有至少一個芳族部分且含有1至3個選自氧、硫及氮之雜原子， - 「環烷基」意指任何含有3至10個環成員之單環或雙環非芳族碳環基， - 「雜環烷基」意指任何含有3至10個環成員且含有1至3個選自氧、硫及氮之雜原子的單環或雙環非芳族碳環基，其可包括稠環、橋環或螺環系， 如此定義之芳基、雜芳基、環烷基及雜環烷基以及烷基、烯基、炔基、烷氧基可能經1至4個選自以下之基團取代：視情況經取代之直鏈或分支鏈(C1 -C6 )烷基、視情況經取代之直鏈或分支鏈(C2 -C6 )烯基、視情況經取代之直鏈或分支鏈(C2 -C6 )炔基、視情況經取代之直鏈或分支鏈(C1 -C6 )烷氧基、視情況經取代之(C1 -C6 )烷基-S-、羥基、側氧基(或適當時，N -氧化物)、硝基、氰基、-C(O)-OR'、-O-C(O)-R'、-C(O)-NR'R''、-NR'R''、-(C=NR')-OR''、直鏈或分支鏈(C1 -C6 )多鹵烷基、三氟甲氧基或鹵素，應理解，R'及R''彼此獨立地表示氫原子或視情況經取代之直鏈或分支鏈(C1 -C6 )烷基，且應理解，前述可能的取代基之一或多個碳原子可經氘化， 或其對映異構體、非對映異構體或滯轉異構體，或其與醫藥學上可接受之酸或鹼之加成鹽， 及(b)紫杉烷化合物， 用於同時、依序或分開使用。 式(I)之該等化合物、其合成、其在癌症治療中之用途及其醫藥調配物描述於WO 2015/097123、WO 2016/207216、WO 2016/207217、WO 2016/207225、WO 2016/207226及WO 2017/125224中，其內容以引用之方式併入。 在某些實施例中，紫杉烷化合物選自太平洋紫杉醇、多西他賽、卡巴他賽(cabazitaxel)、替司他賽(tesetaxel)、Opaxio® (太平洋紫杉醇聚麩胺酸)、Abraxane® (白蛋白結合型太平洋紫杉醇)、拉洛他賽(larotaxel)、他克普辛(taxoprexin)、BMS-184476、紅豆杉(honhgdoushan) A、紅豆杉B及紅豆杉C及其他。 根據本發明之第一態樣，提供一種組合，其包含： (a)式(II)之MCL-1抑制劑，即式(I)之MCL-1抑制劑之特例：其中： ¨ Z表示氮原子或C-R4 基團， ¨ R1 表示直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、氰基、-NR11 R11 '、-Cy8 或鹵素原子， ¨ R2 、R3 及R4 彼此獨立地表示氫原子、鹵素原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-烷基(C0 -C6 )-NR11 R11 '、-O-Cy1 、-烷基(C0 -C6 )-Cy1 、-烯基(C2 -C6 )-Cy1 、-炔基(C2 -C6 )-Cy1 、-O-烷基(C1 -C6 )-R12 、 -C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 '、-NR11 -C(O)-R11 '、-NR11 -C(O)-OR11 '、-烷基(C1 -C6 )-NR11 -C(O)-R11 '、-SO2 -NR11 R11 '或-SO2 -烷基(C1 -C6 )， 或(R2 ，R3 )、(R3 ，R4 )其中一對取代基與攜載其的碳原子一起形成由5至7個環成員組成之芳族或非芳族環，其可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可經選自以下之基團取代：直鏈或分支鏈(C1 -C6 )烷基基團、-NR13 R13 '、-烷基(C0 -C6 )-Cy1 或側氧基， ¨ R6 及R7 彼此獨立地表示氫原子、鹵素原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-烷基(C0 -C6 )-NR11 R11 '、-O-Cy1 、-烷基(C0 -C6 )-Cy1 、-烯基(C2 -C6 )-Cy1 、-炔基(C2 -C6 )-Cy1 、-O-烷基(C1 -C6 )-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 '、-NR11 -C(O)-R11 '、-NR11 -C(O)-OR11 '、-烷基(C1 -C6 )-NR11 -C(O)-R11 '、-SO2 -NR11 R11 '或-SO2 -烷基(C1 -C6 )， 或(R6 ，R7 )成對取代基，當接枝於兩個相鄰碳原子上時，與攜載其的碳原子一起形成由5至7個環成員組成之芳族或非芳族環，其可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可經選自以下之基團取代：直鏈或分支鏈(C1 -C6 )烷基、-NR13 R13 '、-烷基(C0 -C6 )-Cy1 或側氧基， ¨ R8 表示氫原子、直鏈或分支鏈(C1 -C8 )烷基、芳基、雜芳基、芳基烷基(C1 -C6 )基團或雜芳基烷基(C1 -C6 )基團， ¨ R9 表示氫原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、-Cy2 、-烷基(C1 -C6 )-Cy2 、-烯基(C2 -C6 )-Cy2 、-炔基(C2 -C6 )-Cy2 、-Cy2 -Cy3 、-炔基(C2 -C6 )-O-Cy2 、-Cy2 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy3 、鹵素原子、氰基、-C(O)-R14 或-C(O)-NR14 R14 '， ¨ R11 及R11 '彼此獨立地表示氫原子、視情況經取代之直鏈或分支鏈(C1 -C6 )烷基或-烷基(C0 -C6 )-Cy1 ， 或(R11 ，R11 ')成對取代基與攜載其的氮原子一起形成由5至7個環成員組成之芳族或非芳族環，其中除該氮原子以外可再含有1至3個選自氧、硫及氮之雜原子，應理解所討論的氮可經表示氫原子或直鏈或分支鏈(C1 -C6 )烷基之基團取代，且應理解可能的取代基之一或多個碳原子可經氘化， ¨ R12 表示-Cy5 、-Cy5 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy6 、-Cy5 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy6 、-Cy5 -烷基(C0 -C6 )-NR11 -烷基(C0 -C6 )-Cy6 、 -Cy5 -Cy6 -O-烷基(C0 -C6 )-Cy7 、-C(O)-NR11 R11 '、-NR11 R11 '、-OR11 、 -NR11 -C(O)-R11 '、-O-烷基(C1 -C6 )-OR11 、-SO2 -R11 、-C(O)-OR11 或-NH-C(O)-NH-R11 ， ¨ R13 、R13 '、R14 及R14 '彼此獨立地表示氫原子或視情況經取代之直鏈或分支鏈(C1 -C6 )烷基， ¨ R25 表示氫原子、羥基或羥基(C1 -C6 )烷基， ¨ Cy1 、Cy2 、Cy3 、Cy5 、Cy6 、Cy7 及Cy8 彼此獨立地表示環烷基、雜環烷基、芳基或雜芳基， ¨ n為等於0或1之整數， 應理解： - 「芳基」意指苯基、萘基、聯苯基、茚滿基或茚基， - 「雜芳基」意指任何由5至10個環成員組成之單環或雙環基團，其具有至少一個芳族部分且含有1至3個選自氧、硫及氮之雜原子， - 「環烷基」意指任何含有3至10個環成員之單環或雙環非芳族碳環基， - 「雜環烷基」意指任何含有3至10個環成員且含有1至3個選自氧、硫及氮之雜原子的單環或雙環非芳族碳環基，其可包括稠環、橋環或螺環系， 如此定義之芳基、雜芳基、環烷基及雜環烷基以及烷基、烯基、炔基、烷氧基可能經1至4個選自以下之基團取代：視情況經取代之直鏈或分支鏈(C1 -C6 )烷基、視情況經取代之直鏈或分支鏈(C2 -C6 )烯基、視情況經取代之直鏈或分支鏈(C2 -C6 )炔基、視情況經取代之直鏈或分支鏈(C1 -C6 )烷氧基、視情況經取代之(C1 -C6 )烷基-S-、羥基、側氧基(或適當時，N -氧化物)、硝基、氰基、-C(O)-OR'、-O-C(O)-R'、-C(O)-NR'R''、-NR'R''、-(C=NR')-OR''、直鏈或分支鏈(C1 -C6 )多鹵烷基、三氟甲氧基或鹵素，應理解，R'及R''彼此獨立地表示氫原子或視情況經取代之直鏈或分支鏈(C1 -C6 )烷基，且應理解，前述可能的取代基之一或多個碳原子可經氘化， 或其對映異構體、非對映異構體或滯轉異構體，或其與醫藥學上可接受之酸或鹼之加成鹽， 及(b)紫杉烷化合物， 用於同時、依序或分開使用。 在另一實施例中，本發明提供一種組合，其包含： (a)如本文中所描述之式(I)之MCL-1抑制劑，及 (b)選自太平洋紫杉醇或多西他賽之紫杉烷化合物， 或 (a)如本文中所描述之式(II)之MCL-1抑制劑，及 (b)選自太平洋紫杉醇或多西他賽之紫杉烷化合物， 用於同時、依序或分開使用。 在另一實施例中，本發明提供一種組合，其包含： (a)化合物1：(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸或其醫藥學上可接受之鹽，及 (b)紫杉烷化合物， 用於同時、依序或分開使用。 可替代地，本發明提供一種組合，其包含： (a)化合物2：(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(5-氟呋喃-2-基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[1-(2,2,2-三氟乙基)-1H -吡唑-5-基]甲氧基}苯基)丙酸或其醫藥學上可接受之鹽，及 (b)紫杉烷化合物， 用於同時、依序或分開使用。 在另一實施例中，本發明提供一種如本文所描述之組合用於治療癌症。 在另一實施例中，本發明提供如本文中所描述之組合在製造治療癌症之藥物中的用途。 在另一實施例中，本發明提供一種分開包含或一起包含以下各者之藥劑， (a)如本文中所描述之式(I)之MCL-1抑制劑，及 (b)紫杉烷化合物， 或 (a)如本文中所描述之式(II)之MCL-1抑制劑，及 (b)紫杉烷化合物， 用於同時、依序或分開投與，且其中MCL-1抑制劑及紫杉烷化合物以治療癌症之有效量提供。 在另一實施例中，本發明提供一種治療癌症之方法，其包含向對其有需要之個體投與共同治療有效量之以下各者： (a)如本文中所描述之式(I)之MCL-1抑制劑，及 (b)紫杉烷化合物， 或 (a)如本文中所描述之式(II)之MCL-1抑制劑，及 (b)紫杉烷化合物。 在另一實施例中，MCL-1抑制劑為(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸(化合物1)。 在另一實施例中，MCL-1抑制劑為(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(5-氟呋喃-2-基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[1-(2,2,2-三氟乙基)-1H -吡唑-5-基]甲氧基}苯基)丙酸(化合物2)。 在另一實施例中，紫杉烷化合物為太平洋紫杉醇。 在另一實施例中，紫杉烷化合物為多西他賽。The invention relates to a combination comprising: (a) an MCL-1 inhibitor of formula (I): Wherein: ¨ D represents a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, ¨ E represents a furyl group, thienyl group or pyrrolyl ring, and ¨ X 1 , X 3 , X 4 and X 5 independently represent each other Carbon atom or nitrogen atom, ¨ X 2 represents CR 26 group or nitrogen atom, ¨ It means that the ring is aromatic, ¨ Y represents a nitrogen atom or a CR 3 group, ¨ Z represents a nitrogen atom or a CR 4 group, and ¨ R 1 represents a halogen atom, a linear or branched (C 1 -C 6 ) alkyl group , Straight or branched (C 2 -C 6 ) alkenyl, straight or branched (C 2 -C 6 ) alkynyl, straight or branched (C 1 -C 6 ) polyhaloalkyl, hydroxyl, Hydroxy (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) alkoxy, -S- (C 1 -C 6 ) alkyl, cyano, nitro, -Cy 8 , -Alkyl (C 0 -C 6 ) -NR 11 R 11 ', -O-alkyl (C 1 -C 6 ) -NR 11 R 11 ', -O-alkyl (C 1 -C 6 ) -R 12 , -C (O) -OR 11 , -OC (O) -R 11 , -C (O) -NR 11 R 11 ', -NR 11 -C (O) -R 11 ', -NR 11 -C (O) -OR 11 ', -alkyl (C 1 -C 6 ) -NR 11 -C (O) -R 11 ', -SO 2 -NR 11 R 11 'or -SO 2 -alkyl (C 1 -C 6 ), ¨ R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom, a halogen atom, a straight or branched (C 1 -C 6 ) alkyl group, a straight or branched chain (C 2 -C 6 ) alkenyl, straight or branched (C 2 -C 6 ) alkynyl, straight or branched (C 1 -C 6 ) polyhaloalkyl, hydroxyl, hydroxyl (C 1 -C 6 ) alkane group, a linear or branched (C 1 -C 6) alkoxy , -S- (C 1 -C 6) alkyl, cyano, nitro, - alkyl (C 0 -C 6) -NR 11 R 11 ', -O-Cy 1, - alkyl (C 0 - C 6 ) -Cy 1 , -alkenyl (C 2 -C 6 ) -Cy 1 , -alkynyl (C 1 -C 6 ) -Cy 1 , -O-alkynyl (C 1 -C 6 ) -NR 11 R 11 ', -O-alkyl (C 1 -C 6 ) -R 12 , -C (O) -OR 11 , -OC (O) -R 11 , -C (O) -NR 11 R 11 ', -NR 11 -C (O) -R 11 ', -NR 11 -C (O) -OR 11 ', -alkyl (C 1 -C 6 ) -NR 11 -C (O) -R 11 ',- SO 2 -NR 11 R 11 'or -SO 2 -alkyl (C 1 -C 6 ), or (R 1 , R 2 ), (R 2 , R 3 ), (R 3 , R 4 ), (R 4 , R 5 ) Pairs of substituents together with the carbon atom carrying it form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain 1 to 3 members selected from oxygen, sulfur and nitrogen Heteroatom, it is understood that the resulting ring may be substituted with 1 to 2 groups selected from halogen, straight or branched (C 1 -C 6 ) alkyl, -alkyl (C 0 -C 6 )- NR 11 R 11 ′, -NR 13 R 13 ′, -alkyl (C 0 -C 6 ) -Cy 1 or pendant oxy group, ¨ R 6 and R 7 each independently represent a hydrogen atom, a halogen atom, a straight chain or Branched (C 1 -C 6 ) alkyl, straight or branched (C 2 -C 6 ) alkenyl, straight or branched (C 2 -C 6 ) alkynyl, straight or branched (C 1 -C 6 ) polyhaloalkyl, hydroxyl, straight or branched (C 1 -C 6 ) alkoxy, -S- ( C 1 -C 6 ) alkyl, cyano, nitro, -alkyl (C 0 -C 6 ) -NR 11 R 11 ', -O-alkyl (C 1 -C 6 ) -NR 11 R 11 ' , -O-Cy 1 , -alkyl (C 0 -C 6 ) -Cy 1 , -alkenyl (C 2 -C 6 ) -Cy 1 , -alkynyl (C 2 -C 6 ) -Cy 1 ,- O-alkyl (C 1 -C 6 ) -R 12 , -C (O) -OR 11 , -OC (O) -R 11 , -C (O) -NR 11 R 11 ', -NR 11 -C (O) -R 11 ', -NR 11 -C (O) -OR 11 ', -alkyl (C 1 -C 6 ) -NR 11 -C (O) -R 11 ', -SO 2 -NR 11 R 11 'or -SO 2 -alkyl (C 1 -C 6 ), or (R 6 , R 7 ) pair substituents, when grafted to two adjacent carbon atoms, with the carbon carrying it The atoms together form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. It should be understood that the resulting ring may be Group substitution: linear or branched (C 1 -C 6 ) alkyl, -NR 13 R 13 ', -alkyl (C 0 -C 6 ) -Cy 1 or pendant oxy group, ¨ W represents -CH 2- group, -NH- group or an oxygen atom, ¨ R 8 represents a hydrogen atom, a linear or branched (C 1 -C 8) alkyl, -CHR a R b group, aryl, heteroaryl, arylalkyl (C 1 -C 6) group or heteroarylalkyl (C 1 -C 6 ) Group, ¨ R 9 represents a hydrogen atom, straight or branched (C 1 -C 6 ) alkyl, straight or branched (C 2 -C 6 ) alkenyl, straight or branched (C 2- C 6 ) alkynyl, -Cy 2 , -alkyl (C 1 -C 6 ) -Cy 2 , -alkenyl (C 2 -C 6 ) -Cy 2 , -alkynyl (C 2 -C 6 ) -Cy 2 , -Cy 2 -Cy 3 , -alkynyl (C 2 -C 6 ) -O-Cy 2 , -Cy 2 -alkyl (C 0 -C 6 ) -O-alkyl (C 0 -C 6 ) -Cy 3 , halogen atom, cyano group, -C (O) -R 14 or -C (O) -NR 14 R 14 ′, ¨ R 10 represents a hydrogen atom, a straight chain or a branched chain (C 1 -C 6 ) Alkyl, straight or branched (C 2 -C 6 ) alkenyl, straight or branched (C 2 -C 6 ) alkynyl, arylalkyl (C 1 -C 6 ) group, cycloalkyl Alkyl (C 1 -C 6 ) group, straight or branched (C 1 -C 6 ) polyhaloalkyl or -alkyl (C 1 -C 6 ) -O-Cy 4 , or (R 9 , R 10 ) a pair of substituents, when grafted onto two adjacent carbon atoms, together with the carbon atom carrying it, form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain 1 to 3 selected from oxygen, sulfur and nitrogen Hetero atom, ¨ R 11 and R 11 'independently of each other represent a hydrogen atom, optionally substituted straight or branched chain (C 1 -C 6 ) alkyl or -alkyl (C 0 -C 6 ) -Cy 1 , or (R 11 , R 11 ′) paired substituents together with the nitrogen atom carrying it form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain 1 in addition to the nitrogen atom To 3 heteroatoms selected from oxygen, sulfur and nitrogen, it is understood that the nitrogen in question may be substituted with 1 to 2 groups representing a hydrogen atom or a straight or branched (C 1 -C 6 ) alkyl group, and It should be understood that one or more carbon atoms of possible substituents may be deuterated, ¨ R 12 represents -Cy 5 , -Cy 5 -alkyl (C 0 -C 6 ) -O-alkyl (C 0 -C 6 ) -Cy 6 , -Cy 5 -alkyl (C 0 -C 6 ) -Cy 6 , -Cy 5 -alkyl (C 0 -C 6 ) -NR 11 -alkyl (C 0 -C 6 ) -Cy 6 , -Cy 5 -Cy 6 -O-alkyl (C 0 -C 6 ) -Cy 7 , -Cy 5 -alkyl (C 0 -C 6 ) -O-alkyl (C 0 -C 6 )- Cy 9 , -Cy 5 -alkyl (C 0 -C 6 ) -Cy 9 , -NH-C (O) -NH-R 11 , -Cy 5 -alkyl (C 0 -C 6 ) -NR 11- Alkyl (C 0 -C 6 ) -Cy 9 , -C (O) -NR 11 R 11 ', -NR 11 R 11 ', -OR 11 , -NR 11 -C (O) -R 11 ',- O- alkyl (C 1 -C 6) -OR 11 -SO 2 -R 11, -C (O ) -OR 11, , or , ¨ The ammonium thus defined may exist in the form of zwitterions or have a monovalent anion counter ion, ¨ R 13 , R 13 ′, R 14 and R 14 ′ each independently represent a hydrogen atom or optionally substituted linear or Branched (C 1 -C 6 ) alkyl, ¨ R a represents a hydrogen atom or a straight or branched (C 1 -C 6 ) alkyl, ¨ R b represents -OC (O) -OR c group,- OC (O) -NR c R c 'group or -OP (O) (OR c ) 2 group, ¨ R c and R c ' each independently represent a hydrogen atom, a straight chain or a branched chain (C 1 -C 8 ) alkyl, cycloalkyl, (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) alkoxycarbonyl (C 1 -C 6 ) alkyl , Or (R c , R c ') paired substituents together with the nitrogen atom carrying it form a non-aromatic ring consisting of 5 to 7 ring members, which may contain 1 to 3 selected from nitrogen atoms Heteroatoms of oxygen and nitrogen, it should be understood that the nitrogen in question may be substituted by a group representing a linear or branched (C 1 -C 6 ) alkyl group, ¨ Cy 1 , Cy 2 , Cy 3 , Cy 4 , Cy 5 , Cy 6 , Cy 7 , Cy 8 and Cy 10 each independently represent a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, and ¨ Cy 9 represents , Or Cy 9 represents a heteroaryl group substituted with a group selected from: -OP (O) (OR 20 ) 2 ; -OP (O) (O - M + ) 2 ;-(CH 2 ) p -O -(CHR 18 -CHR 19 -O) q -R 20 ; hydroxyl; hydroxyl (C 1 -C 6 ) alkyl;-(CH 2 ) r -U- (CH 2 ) s -heterocycloalkyl ; or- U- (CH 2 ) q -NR 21 R 21 ', ¨ R 15 represents a hydrogen atom;-(CH 2 ) p -O- (CHR 18 -CHR 19 -O) q -R 20 group; straight or branched Chain (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl; -U- (CH 2 ) q -NR 21 R 21 'group; or-(CH 2 ) r -U- (CH 2 ) s -heterocycloalkyl, ¨ R 16 represents a hydrogen atom; hydroxy; hydroxy (C 1 -C 6 ) alkyl;-(CH 2 ) r -U- (CH 2 ) s -heterocycloalkyl; CH 2 ) r -UVOP (O) (OR 20 ) 2 group; -OP (O) (O - M + ) 2 group;-(CH 2 ) p -O- (CHR 18 -CHR 19 -O) q -R 20 group;-(CH 2 ) p -OC (O) -NR 22 R 23 group; or -U- (CH 2 ) q -NR 21 R 21 'group, ¨ R 17 represents a hydrogen atom ;-(CH 2 ) p -O- (CHR 18 -CHR 19 -O) q -R 20 group; -OP (O) (OR 20 ) 2 group; -OP (O) (O - M + ) 2 groups; hydroxyl; hydroxyl (C 1 -C 6 ) alkyl;-(CH 2 ) r -U- (CH 2 ) s -heterocycloalkyl; -U- (CH 2 ) q -NR 21 R 21 'Group; or Uronic acid, ¨ M + represents a pharmaceutically acceptable monovalent cation, ¨ U represents a bond or an oxygen atom, ¨ V represents-(CH 2 ) s -group or -C (O)-group, ¨ R 18 Represents a hydrogen atom or (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl, ¨ R 19 represents a hydrogen atom or hydroxy (C 1 -C 6 ) alkyl, and ¨ R 20 represents a hydrogen atom or straight Chain or branched (C 1 -C 6 ) alkyl, ¨ R 21 and R 21 'independently of each other represent a hydrogen atom, straight or branched (C 1 -C 6 ) alkyl or hydroxy (C 1 -C 6 ) Alkyl, or (R 21 , R 21 ′) paired substituents together with the nitrogen atom carrying it to form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, wherein It further contains 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. It should be understood that the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group. ¨ R 22 (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl,-(CH 2 ) p -NR 24 R 24 'group or-(CH 2 ) p -O- (CHR 18 -CHR 19 -O) q -R 20 group, ¨ R 23 represents a hydrogen atom or (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl, or (R 22 , R 23 ) paired substituents With its carrying nitrogen Together form an aromatic or non-aromatic ring consisting of 5 to 18 ring members, which may contain 1 to 5 heteroatoms selected from oxygen, sulfur, and nitrogen in addition to the nitrogen atom. It should be understood that the resulting ring may be represented by Hydrogen atom, linear or branched (C 1 -C 6 ) alkyl or heterocycloalkyl group substitution, ¨ R 24 and R 24 'independently of each other represent a hydrogen atom or a straight or branched chain (C 1- C 6 ) alkyl, or (R 24 , R 24 ') paired substituents together with the nitrogen atom carrying it to form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, in which the nitrogen atom is removed In addition, it may further contain 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. It should be understood that the resulting ring may be substituted with a group representing a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group. ¨ R 25 represents a hydrogen atom, a hydroxyl group or a hydroxy (C 1 -C 6 ) alkyl group, ¨ R 26 represents a hydrogen atom, a halogen atom, a linear or branched (C 1 -C 6 ) alkyl group, or a cyano group, ¨ R 27 represents a hydrogen atom or a linear or branched (C 1 -C 6) alkyl, ¨ R 28 represents -OP (O) (O -) (O -) group, -OP (O) (O - ) (oR 30) groups, -OP (O) (OR 30 ) (OR 30 ') groups, -O-SO 2 -O - group, -O-SO 2 -OR 3 0 group, -Cy 10 , -OC (O) -R 29 group, -OC (O) -OR 29 group, or -OC (O) -NR 29 R 29 'group; ¨ R 29 and R 29 'Independent of each other means a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl or a linear or branched amine (C 1 -C 6 ) alkyl, ¨ R 30 and R 30 ' are independent of each other Represents a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl or arylalkyl (C 1 -C 6 ) group, ¨ n is an integer equal to 0 or 1, and ¨ p is equal to 0, 1 Or an integer of 2, ¨ q is an integer equal to 1, 2, 3, or 4 and ¨ r and s are independently integers equal to 0 or 1, it should be understood:-"aryl" means phenyl, naphthyl, Phenyl, indanyl or indenyl, "heteroaryl" means any monocyclic or bicyclic group consisting of 5 to 10 ring members, which has at least one aromatic moiety and contains 1 to 3 selected from Heteroatoms of oxygen, sulfur and nitrogen,-"cycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members,-"heterocycloalkyl" means any containing 3 to 10 A monocyclic or bicyclic non-aromatic carbocyclic group of 10 ring members and containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, which may include fused Ring, bridged ring or spiro ring system, so defined aryl, heteroaryl, cycloalkyl and heterocycloalkyl and alkyl, alkenyl, alkynyl, alkoxy may be selected from 1 to 4 Group substitution: optionally substituted straight or branched (C 1 -C 6 ) alkyl, optionally substituted straight or branched (C 2 -C 6 ) alkenyl, optionally substituted straight Chain or branched (C 2 -C 6 ) alkynyl, optionally substituted straight or branched (C 1 -C 6 ) alkoxy, optionally (C 1 -C 6 ) alkyl- S-, hydroxyl, pendant oxygen (or N -oxide if appropriate), nitro, cyano, -C (O) -OR ', -OC (O) -R', -C (O) -NR 'R'',-NR'R'',-(C = NR')-OR '', linear or branched (C 1 -C 6 ) polyhaloalkyl, trifluoromethoxy or halogen, should be It is understood that R ′ and R ″ independently of each other represent a hydrogen atom or optionally substituted linear or branched (C 1 -C 6 ) alkyl group, and it should be understood that one or more carbons of the foregoing possible substituents Atoms may be deuterated, or their enantiomers, diastereomers or atropisomers, or their addition salts with pharmaceutically acceptable acids or bases, and (b) taxus Alkylation For simultaneous, sequential or separate use. The compounds of formula (I), their synthesis, their use in cancer treatment and their pharmaceutical formulations are described in WO 2015/097123, WO 2016/207216, WO 2016/207217, WO 2016/207225, WO 2016/207226 And WO 2017/125224, the contents of which are incorporated by reference. In certain embodiments, the taxane compound is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, tesetaxel, Opaxio® (paclitaxel polyglutamic acid), Abraxane® ( Albumin-bound paclitaxel), larotaxel, taxoprexin, BMS-184476, honhgdoushan A, yew B, and yew C and others. According to a first aspect of the present invention, there is provided a combination comprising: (a) an MCL-1 inhibitor of formula (II), that is, a special case of an MCL-1 inhibitor of formula (I): Where: ¨ Z represents a nitrogen atom or a CR 4 group, and ¨ R 1 represents a straight or branched (C 1 -C 6 ) alkyl, straight or branched (C 2 -C 6 ) alkenyl, straight or Branched (C 2 -C 6 ) alkynyl, straight or branched (C 1 -C 6 ) alkoxy, -S- (C 1 -C 6 ) alkyl, straight or branched (C 1- C 6 ) polyhaloalkyl, hydroxy, cyano, -NR 11 R 11 ', -Cy 8 or halogen atom, ¨ R 2 , R 3 and R 4 each independently represent a hydrogen atom, a halogen atom, a straight chain or a branch (C 1 -C 6 ) alkyl, straight or branched (C 2 -C 6 ) alkenyl, straight or branched (C 2 -C 6 ) alkynyl, straight or branched (C 1- C 6 ) polyhaloalkyl, hydroxy, linear or branched (C 1 -C 6 ) alkoxy, -S- (C 1 -C 6 ) alkyl, cyano, nitro, -alkyl (C 0 -C 6 ) -NR 11 R 11 ', -O-Cy 1 , -alkyl (C 0 -C 6 ) -Cy 1 , -alkenyl (C 2 -C 6 ) -Cy 1 , -alkynyl ( C 2 -C 6 ) -Cy 1 , -O-alkyl (C 1 -C 6 ) -R 12 , -C (O) -OR 11 , -OC (O) -R 11 , -C (O)- NR 11 R 11 ', -NR 11 -C (O) -R 11 ', -NR 11 -C (O) -OR 11 ', -alkyl (C 1 -C 6 ) -NR 11 -C (O) -R 11 ', -SO 2 -NR 11 R 11 ' or -SO 2 -alkyl (C 1 -C 6 ), or ( R 2 , R 3 ), (R 3 , R 4 ) in which a pair of substituents together with the carbon atom carrying it form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it should be understood that the resulting ring may be substituted with a group selected from the group consisting of a straight or branched (C 1 -C 6 ) alkyl group, -NR 13 R 13 ', -Alkyl (C 0 -C 6 ) -Cy 1 or pendant oxy, R 6 and R 7 each independently represent a hydrogen atom, a halogen atom, a linear or branched (C 1 -C 6 ) alkyl group , Straight or branched (C 2 -C 6 ) alkenyl, straight or branched (C 2 -C 6 ) alkynyl, straight or branched (C 1 -C 6 ) polyhaloalkyl, hydroxyl, Linear or branched (C 1 -C 6 ) alkoxy, -S- (C 1 -C 6 ) alkyl, cyano, nitro, -alkyl (C 0 -C 6 ) -NR 11 R 11 ', -O-Cy 1 , -alkyl (C 0 -C 6 ) -Cy 1 , -alkenyl (C 2 -C 6 ) -Cy 1 , -alkynyl (C 2 -C 6 ) -Cy 1 , -O-alkyl (C 1 -C 6 ) -R 12 , -C (O) -OR 11 , -OC (O) -R 11 , -C (O) -NR 11 R 11 ', -NR 11- C (O) -R 11 ', -NR 11 -C (O) -OR 11 ', -alkyl (C 1 -C 6 ) -NR 11 -C (O) -R 11 ', -SO 2 -NR 11 R 11 'or -SO 2 -alkyl (C 1 -C 6 ), Or (R 6 , R 7 ) paired substituents, when grafted on two adjacent carbon atoms, together with the carbon atom carrying it, form an aromatic or non-aromatic group consisting of 5 to 7 ring members A ring, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. It should be understood that the resulting ring may be substituted with a group selected from the group consisting of straight or branched (C 1 -C 6 ) alkyl, -NR 13 R 13 ', -alkyl (C 0 -C 6 ) -Cy 1 or pendant oxy group, and ¨ R 8 represents a hydrogen atom, a linear or branched (C 1 -C 8 ) alkyl group, an aryl group, Heteroaryl, arylalkyl (C 1 -C 6 ) group or heteroarylalkyl (C 1 -C 6 ) group, ¨ R 9 represents a hydrogen atom, straight chain or branched chain (C 1 -C 6 ) Alkyl, straight or branched (C 2 -C 6 ) alkenyl, straight or branched (C 2 -C 6 ) alkynyl, -Cy 2 , -alkyl (C 1 -C 6 )- Cy 2 , -alkenyl (C 2 -C 6 ) -Cy 2 , -alkynyl (C 2 -C 6 ) -Cy 2 , -Cy 2 -Cy 3 , -alkynyl (C 2 -C 6 ) -O -Cy 2 , -Cy 2 -alkyl (C 0 -C 6 ) -O-alkyl (C 0 -C 6 ) -Cy 3 , halogen atom, cyano, -C (O) -R 14 or -C (O) -NR 14 R 14 ′, ¨ R 11 and R 11 ′ each independently represent a hydrogen atom, optionally substituted straight or branched chain (C 1- C 6 ) alkyl or -alkyl (C 0 -C 6 ) -Cy 1 , or (R 11 , R 11 ′) paired substituents together with the nitrogen atom carrying it to form 5 to 7 ring members An aromatic or non-aromatic ring, in which in addition to the nitrogen atom may further contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it should be understood that the nitrogen in question may be represented by a hydrogen atom or a straight or branched chain (C 1 -C 6 ) alkyl group substitution, and it should be understood that one or more carbon atoms of possible substituents may be deuterated, ¨ R 12 represents -Cy 5 , -Cy 5 -alkyl (C 0 -C 6 ) -O-alkyl (C 0 -C 6 ) -Cy 6 , -Cy 5 -alkyl (C 0 -C 6 ) -O-alkyl (C 0 -C 6 ) -Cy 6 ,- Cy 5 -alkyl (C 0 -C 6 ) -NR 11 -alkyl (C 0 -C 6 ) -Cy 6 , -Cy 5 -Cy 6 -O-alkyl (C 0 -C 6 ) -Cy 7 , -C (O) -NR 11 R 11 ', -NR 11 R 11 ', -OR 11 , -NR 11 -C (O) -R 11 ', -O-alkyl (C 1 -C 6 )- OR 11 , -SO 2 -R 11 , -C (O) -OR 11 or -NH-C (O) -NH-R 11 , ¨ R 13 , R 13 ′, R 14 and R 14 ′ are represented independently of each other Hydrogen atom or optionally substituted linear or branched (C 1 -C 6 ) alkyl, ¨ R 25 represents a hydrogen atom, a hydroxyl group or a hydroxy (C 1 -C 6 ) alkyl group, ¨ Cy 1 , Cy 2 , Cy 3 , Cy 5 , Cy 6 , Cy 7 and Cy 8 independently represent cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and ¨ n is an integer equal to 0 or 1, it should be understood:-""Aryl" means phenyl, naphthyl, biphenyl, indanyl or indenyl,-"heteroaryl" means any monocyclic or bicyclic group consisting of 5 to 10 ring members, which has at least An aromatic moiety and containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen,-"cycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members,- "Heterocycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members and 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which may include fused rings, Bridged or spiro ring systems, so defined aryl, heteroaryl, cycloalkyl, and heterocycloalkyl and alkyl, alkenyl, alkynyl, and alkoxy groups may have from 1 to 4 groups selected from Substitution: optionally substituted straight or branched (C 1 -C 6 ) alkyl, optionally substituted straight or branched (C 2 -C 6 ) alkenyl, optionally substituted straight or branched (C 2 -C 6) alkynyl The optionally substituted straight or branched (C 1 -C 6) alkoxy, the optionally substituted (C 1 -C 6) alkyl -S-, hydroxy, oxo (or, where appropriate, N -Oxide), nitro, cyano, -C (O) -OR ', -OC (O) -R', -C (O) -NR'R '', -NR'R '',-( C = NR ')-OR'', linear or branched (C 1 -C 6 ) polyhaloalkyl, trifluoromethoxy or halogen, it should be understood that R ′ and R ″ independently represent a hydrogen atom Or optionally substituted linear or branched (C 1 -C 6 ) alkyl, and it should be understood that one or more of the carbon atoms of the foregoing possible substituents may be deuterated, or an enantiomer thereof, Diastereomers or atropisomers, or addition salts thereof with pharmaceutically acceptable acids or bases, and (b) taxane compounds, for simultaneous, sequential or separate use. In another embodiment, the invention provides a combination comprising: (a) an MCL-1 inhibitor of formula (I) as described herein, and (b) selected from the group consisting of paclitaxel or docetaxel Taxane compounds, or (a) an MCL-1 inhibitor of formula (II) as described herein, and (b) a taxane compound selected from paclitaxel or docetaxel for simultaneous, Orderly or separately. In another embodiment, the present invention provides a combination comprising: (a) compound 1: (2 R ) -2-{[(5 S a ) -5- {3-chloro-2-methyl-4 -[2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3- d ] pyrimidin-4-yl] oxy } -3- (2-{[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propionic acid or a pharmaceutically acceptable salt thereof, and (b) violet Taxane compounds for simultaneous, sequential or separate use. Alternatively, the present invention provides a combination comprising: (a) compound 2: (2 R ) -2-{[(5 S a ) -5- {3-chloro-2-methyl-4- [2 -(4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl) thieno [2,3- d ] pyrimidin-4-yl] oxy } -3- (2-{[1- (2,2,2-trifluoroethyl) -1 H -pyrazol-5-yl] methoxy} phenyl) propionic acid or its pharmaceutically acceptable Salts, and (b) taxane compounds, for simultaneous, sequential or separate use. In another embodiment, the invention provides a combination as described herein for treating cancer. In another embodiment, the invention provides the use of a combination as described herein in the manufacture of a medicament for the treatment of cancer. In another embodiment, the present invention provides a medicament separately or together comprising (a) an MCL-1 inhibitor of formula (I) as described herein, and (b) a taxane compound , Or (a) an MCL-1 inhibitor of formula (II) as described herein, and (b) a taxane compound for simultaneous, sequential or separate administration, and wherein the MCL-1 inhibitor and The taxane compound is provided in an effective amount to treat cancer. In another embodiment, the invention provides a method of treating cancer, comprising administering to a subject in need thereof a co-therapeutic effective amount of each of: (a) a compound of formula (I) as described herein MCL-1 inhibitor, and (b) a taxane compound, or (a) an MCL-1 inhibitor of formula (II) as described herein, and (b) a taxane compound. In another embodiment, the MCL-1 inhibitor is (2 R ) -2-{[((5 S a ) -5- {3-chloro-2-methyl-4- [2- (4-methyl Piperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3- d ] pyrimidin-4-yl] oxy} -3- (2-{[ 2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propionic acid (Compound 1). In another embodiment, the MCL-1 inhibitor is (2 R ) -2-{[((5 S a ) -5- {3-chloro-2-methyl-4- [2- (4-methyl Piperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl) thieno [2,3- d ] pyrimidin-4-yl] oxy} -3- (2 - {[1- (2,2,2-trifluoroethyl) -1 H - pyrazol-5-yl] methoxy} phenyl) propanoic acid (compound 2). In another embodiment, the taxane compound is paclitaxel. In another embodiment, the taxane compound is docetaxel.

因此本發明在實施例E1中提供一種組合，其包含： (a)式(I)之MCL-1抑制劑：其中： ¨ D表示環烷基、雜環烷基、芳基或雜芳基， ¨ E表示呋喃基、噻吩基或吡咯基環， ¨ X1 、X3 、X4 及X5 彼此獨立地表示碳原子或氮原子， ¨ X2 表示C-R26 基團或氮原子， ¨意指環為芳族的， ¨ Y表示氮原子或C-R3 基團， ¨ Z表示氮原子或C-R4 基團， ¨ R1 表示鹵素原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、羥基(C1 -C6 )烷基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-Cy8 、-烷基(C0 -C6 )-NR11 R11 '、-O-烷基(C1 -C6 )-NR11 R11 '、 -O-烷基(C1 -C6 )-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 '、-NR11 -C(O)-R11 '、-NR11 -C(O)-OR11 '、-烷基(C1 -C6 )-NR11 -C(O)-R11 '、-SO2 -NR11 R11 '或-SO2 -烷基(C1 -C6 )， ¨ R2 、R3 、R4 及R5 彼此獨立地表示氫原子、鹵素原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、羥基(C1 -C6 )烷基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-烷基(C0 -C6 )-NR11 R11 '、 -O-Cy1 、-烷基(C0 -C6 )-Cy1 、-烯基(C2 -C6 )-Cy1 、-炔基(C2 -C6 )-Cy1 、-O-烷基(C1 -C6 )-NR11 R11 '、-O-烷基(C1 -C6 )-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 '、-NR11 -C(O)-R11 '、-NR11 -C(O)-OR11 '、-烷基(C1 -C6 )-NR11 -C(O)-R11 '、-SO2 -NR11 R11 '或-SO2 -烷基(C1 -C6 )， 或(R1 ，R2 )、(R2 ，R3 )、(R3 ，R4 )、(R4 ，R5 )成對取代基與攜載其的碳原子一起形成由5至7個環成員組成之芳族或非芳族環，其可含有1至3個選自氧、硫及氮的雜原子，應理解，所得環可經1至2個選自以下之基團取代：鹵素、直鏈或分支鏈(C1 -C6 )烷基、-烷基(C0 -C6 )-NR11 R11 '、 -NR13 R13 '、-烷基(C0 -C6 )-Cy1 或側氧基， ¨ R6 及R7 彼此獨立地表示氫原子、鹵素原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-烷基(C0 -C6 )-NR11 R11 '、-O-烷基(C1 -C6 )-NR11 R11 '、 -O-Cy1 、-烷基(C0 -C6 )-Cy1 、-烯基(C2 -C6 )-Cy1 、-炔基(C2 -C6 )-Cy1 、-O-烷基(C1 -C6 )-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 '、-NR11 -C(O)-R11 '、-NR11 -C(O)-OR11 '、-烷基(C1 -C6 )-NR11 -C(O)-R11 '、-SO2 -NR11 R11 '或-SO2 -烷基(C1 -C6 )， 或(R6 ，R7 )成對取代基，當接枝於兩個相鄰碳原子上時，與攜載其的碳原子一起形成由5至7個環成員組成之芳族或非芳族環，其可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可經選自以下之基團取代：直鏈或分支鏈(C1 -C6 )烷基、-NR13 R13 '、-烷基(C0 -C6 )-Cy1 或側氧基， ¨ W表示-CH2 -基團、-NH-基團或氧原子， ¨ R8 表示氫原子、直鏈或分支鏈(C1 -C8 )烷基、-CHRa Rb 基團、芳基、雜芳基、芳基烷基(C1 -C6 )基團或雜芳基烷基(C1 -C6 )基團， ¨ R9 表示氫原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、-Cy2 、-烷基(C1 -C6 )-Cy2 、-烯基(C2 -C6 )-Cy2 、-炔基(C2 -C6 )-Cy2 、-Cy2 -Cy3 、-炔基(C2 -C6 )-O-Cy2 、-Cy2 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy3 、鹵素原子、氰基、-C(O)-R14 或-C(O)-NR14 R14 '， ¨ R10 表示氫原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、芳基烷基(C1 -C6 )基團、環烷基烷基(C1 -C6 )基團、直鏈或分支鏈(C1 -C6 )多鹵烷基或-烷基(C1 -C6 )-O-Cy4 ， 或(R9 ，R10 )成對取代基，當接枝於兩個相鄰碳原子上時，與攜載其的碳原子一起形成由5至7個環成員組成之芳族或非芳族環，其可含有1至3個選自氧、硫及氮之雜原子， ¨ R11 及R11 '彼此獨立地表示氫原子、視情況經取代之直鏈或分支鏈(C1 -C6 )烷基或-烷基(C0 -C6 )-Cy1 ， 或(R11 ，R11 ')成對取代基與攜載其的氮原子一起形成由5至7個環成員組成之芳族或非芳族環，其中除該氮原子以外可再含有1至3個選自氧、硫及氮之雜原子，應理解所討論的氮可經1至2個表示氫原子或直鏈或分支鏈(C1 -C6 )烷基之基團取代，且應理解可能的取代基之一或多個碳原子可經氘化， ¨ R12 表示-Cy5 、-Cy5 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy6 、-Cy5 -烷基(C0 -C6 )-Cy6 、-Cy5 -烷基(C0 -C6 )-NR11 -烷基(C0 -C6 )-Cy6 、-Cy5 -Cy6 -O-烷基(C0 -C6 )-Cy7 、-Cy5 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy9 、-Cy5 -烷基(C0 -C6 )-Cy9 、-NH-C(O)-NH-R11 、-Cy5 -烷基(C0 -C6 )-NR11 -烷基(C0 -C6 )-Cy9 、-C(O)-NR11 R11 '、-NR11 R11 '、-OR11 、-NR11 -C(O)-R11 '、-O-烷基(C1 -C6 )-OR11 、-SO2 -R11 、-C(O)-OR11 、、或， 如此定義之銨有可能以兩性離子之形式存在或具有單價陰離子相對離子， ¨ R13 、R13 '、R14 及R14 '彼此獨立地表示氫原子或視情況經取代之直鏈或分支鏈(C1 -C6 )烷基， ¨ Ra 表示氫原子或直鏈或分支鏈(C1 -C6 )烷基， ¨ Rb 表示-O-C(O)-O-Rc 基團、-O-C(O)-NRc Rc '基團或-O-P(O)(ORc )2 基團， ¨ Rc 及Rc '彼此獨立地表示氫原子、直鏈或分支鏈(C1 -C8 )烷基、環烷基、(C1 -C6 )烷氧基(C1 -C6 )烷基、或(C1 -C6 )烷氧基羰基(C1 -C6 )烷基， 或(Rc ，Rc ')成對取代基與攜載其的氮原子一起形成由5至7個環成員組成之非芳族環，其中除該氮原子以外可再含有1至3個選自氧及氮之雜原子，應理解，所討論之氮可經表示直鏈或分支鏈(C1 -C6 )烷基之基團取代， ¨ Cy1 、Cy2 、Cy3 、Cy4 、Cy5 、Cy6 、Cy7 、Cy8 及Cy10 彼此獨立地表示環烷基、雜環烷基、芳基或雜芳基， ¨ Cy9 表示， 或Cy9 表示經選自以下之基團取代之雜芳基：-O-P(O)(OR20 )2 ；-O-P(O)(O- M+ )2 ；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 ；羥基；羥基(C1 -C6 )烷基；-(CH2 )r -U-(CH2 )s -雜環烷基；或-U-(CH2 )q -NR21 R21 '， ¨ R15 表示氫原子；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；直鏈或分支鏈(C1 -C6 )烷氧基(C1 -C6 )烷基；-U-(CH2 )q -NR21 R21 '基團；或-(CH2 )r -U-(CH2 )s -雜環烷基， ¨ R16 表示氫原子；羥基；羥基(C1 -C6 )烷基；-(CH2 )r -U-(CH2 )s -雜環烷基；(CH2 )r -U-V-O-P(O)(OR20 )2 基團；-O-P(O)(O- M+ )2 基團；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；-(CH2 )p -O-C(O)-NR22 R23 基團；或-U-(CH2 )q -NR21 R21 '基團， ¨ R17 表示氫原子；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；-O-P(O)(OR20 )2 基團；-O-P(O)(O- M+ )2 基團；羥基；羥基(C1 -C6 )烷基；-(CH2 )r -U-(CH2 )s -雜環烷基；-U-(CH2 )q -NR21 R21 '基團；或醛糖酸， ¨ M+ 表示醫藥學上可接受之單價陽離子， ¨ U表示鍵或氧原子， ¨ V表示-(CH2 )s -基團或-C(O)-基團， ¨ R18 表示氫原子或(C1 -C6 )烷氧基(C1 -C6 )烷基， ¨ R19 表示氫原子或羥基(C1 -C6 )烷基， ¨ R20 表示氫原子或直鏈或分支鏈(C1 -C6 )烷基， ¨ R21 及R21 '彼此獨立地表示氫原子、直鏈或分支鏈(C1 -C6 )烷基或羥基(C1 -C6 )烷基， 或(R21 ，R21 ')成對取代基與攜載其的氮原子一起形成由5至7個環成員組成之芳族或非芳族環，其中除該氮原子以外可再含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可經表示氫原子或直鏈或分支鏈(C1 -C6 )烷基之基團取代， ¨ R22 表示(C1 -C6 )烷氧基(C1 -C6 )烷基、-(CH2 )p -NR24 R24 '基團或 -(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團， ¨ R23 表示氫原子或(C1 -C6 )烷氧基(C1 -C6 )烷基， 或(R22 ，R23 )成對取代基與攜載其的氮原子一起形成由5至18個環成員組成之芳族或非芳族環，其除氮原子以外可含有1至5個選自氧、硫及氮之雜原子，應理解，所得環可經表示氫原子、直鏈或分支鏈(C1 -C6 )烷基或雜環烷基之基團取代， ¨ R24 及R24 '彼此獨立地表示氫原子或直鏈或分支鏈(C1 -C6 )烷基， 或(R24 ，R24 ')成對取代基與攜載其的氮原子一起形成由5至7個環成員組成之芳族或非芳族環，其中除該氮原子以外可再含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可經表示氫原子或直鏈或分支鏈(C1 -C6 )烷基之基團取代， ¨ R25 表示氫原子、羥基或羥基(C1 -C6 )烷基， ¨ R26 表示氫原子、鹵素原子、直鏈或分支鏈(C1 -C6 )烷基或氰基， ¨ R27 表示氫原子或直鏈或分支鏈(C1 -C6 )烷基， ¨ R28 表示-O-P(O)(O- )(O- )基團、-O-P(O)(O- )(OR30 )基團、-O-P(O)(OR30 )(OR30 ')基團、-O-SO2 -O- 基團、-O-SO2 -OR30 基團、-Cy10 、 -O-C(O)-R29 基團、-O-C(O)-OR29 基團或-O-C(O)-NR29 R29 '基團； ¨ R29 及R29 '彼此獨立地表示氫原子、直鏈或分支鏈(C1 -C6 )烷基或直鏈或分支鏈胺基(C1 -C6 )烷基， ¨ R30 及R30 '彼此獨立地表示氫原子、直鏈或分支鏈(C1 -C6 )烷基或芳基烷基(C1 -C6 )基團， ¨ n為等於0或1之整數， ¨ p為等於0、1或2之整數， ¨ q為等於1、2、3或4之整數， ¨ r及s獨立地為等於0或1之整數， 應理解： - 「芳基」意指苯基、萘基、聯苯基、茚滿基或茚基， - 「雜芳基」意指任何由5至10個環成員組成之單環或雙環基團，其具有至少一個芳族部分且含有1至3個選自氧、硫及氮之雜原子， - 「環烷基」意指任何含有3至10個環成員之單環或雙環非芳族碳環基， - 「雜環烷基」意指任何含有3至10個環成員且含有1至3個選自氧、硫及氮之雜原子的單環或雙環非芳族碳環基，其可包括稠環、橋環或螺環系， 如此定義之芳基、雜芳基、環烷基及雜環烷基以及烷基、烯基、炔基、烷氧基可能經1至4個選自以下之基團取代：視情況經取代之直鏈或分支鏈(C1 -C6 )烷基、視情況經取代之直鏈或分支鏈(C2 -C6 )烯基、視情況經取代之直鏈或分支鏈(C2 -C6 )炔基、視情況經取代之直鏈或分支鏈(C1 -C6 )烷氧基、視情況經取代之(C1 -C6 )烷基-S-、羥基、側氧基(或適當時，N -氧化物)、硝基、氰基、-C(O)-OR'、-O-C(O)-R'、-C(O)-NR'R''、-NR'R''、-(C=NR')-OR''、直鏈或分支鏈(C1 -C6 )多鹵烷基、三氟甲氧基或鹵素，應理解，R'及R''彼此獨立地表示氫原子或視情況經取代之直鏈或分支鏈(C1 -C6 )烷基，且應理解，前述可能的取代基之一或多個碳原子可經氘化， 或其對映異構體、非對映異構體或滯轉異構體，或其與醫藥學上可接受之酸或鹼之加成鹽， 及(b)紫杉烷化合物， 用於同時、依序或分開使用。 本文描述本發明之進一步所列舉的實施例(E)。應認識到在各實施例中指定之特徵可與其他指定特徵組合，以提供本發明之其他實施例。 E2.根據E1之組合，其包含： (a)式(II)之MCL-1抑制劑，即式(I)之MCL-1抑制劑之特例：其中： ¨ Z表示氮原子或C-R4 基團， ¨ R1 表示直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、氰基、-NR11 R11 '、-Cy8 或鹵素原子， ¨ R2 、R3 及R4 彼此獨立地表示氫原子、鹵素原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-烷基(C0 -C6 )-NR11 R11 '、-O-Cy1 、-烷基(C0 -C6 )-Cy1 、-烯基(C2 -C6 )-Cy1 、-炔基(C2 -C6 )-Cy1 、-O-烷基(C1 -C6 )-R12 、 -C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 '、-NR11 -C(O)-R11 '、-NR11 -C(O)-OR11 '、-烷基(C1 -C6 )-NR11 -C(O)-R11 '、-SO2 -NR11 R11 '或-SO2 -烷基(C1 -C6 )， 或(R2 ，R3 )、(R3 ，R4 )其中一對取代基與攜載其的碳原子一起形成由5至7個環成員組成之芳族或非芳族環，其可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可經選自以下之基團取代：直鏈或分支鏈(C1 -C6 )烷基基團、-NR13 R13 '、-烷基(C0 -C6 )-Cy1 或側氧基， ¨ R6 及R7 彼此獨立地表示氫原子、鹵素原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、直鏈或分支鏈(C1 -C6 )多鹵烷基、羥基、直鏈或分支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-烷基(C0 -C6 )-NR11 R11 '、-O-Cy1 、-烷基(C0 -C6 )-Cy1 、 -烯基(C2 -C6 )-Cy1 、-炔基(C2 -C6 )-Cy1 、-O-烷基(C1 -C6 )-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 '、-NR11 -C(O)-R11 '、-NR11 -C(O)-OR11 '、-烷基(C1 -C6 )-NR11 -C(O)-R11 '、-SO2 -NR11 R11 '或-SO2 -烷基(C1 -C6 )， 或(R6 ，R7 )成對取代基，當接枝於兩個相鄰碳原子上時，與攜載其的碳原子一起形成由5至7個環成員組成之芳族或非芳族環，其可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可經選自以下之基團取代：直鏈或分支鏈(C1 -C6 )烷基、-NR13 R13 '、-烷基(C0 -C6 )-Cy1 或側氧基， ¨ R8 表示氫原子、直鏈或分支鏈(C1 -C8 )烷基、芳基、雜芳基、芳基烷基(C1 -C6 )基團或雜芳基烷基(C1 -C6 )基團， ¨ R9 表示氫原子、直鏈或分支鏈(C1 -C6 )烷基、直鏈或分支鏈(C2 -C6 )烯基、直鏈或分支鏈(C2 -C6 )炔基、-Cy2 、-烷基(C1 -C6 )-Cy2 、-烯基(C2 -C6 )-Cy2 、-炔基(C2 -C6 )-Cy2 、-Cy2 -Cy3 、-炔基(C2 -C6 )-O-Cy2 、-Cy2 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy3 、鹵素原子、氰基、-C(O)-R14 或-C(O)-NR14 R14 '， ¨ R11 及R11 '彼此獨立地表示氫原子、視情況經取代之直鏈或分支鏈(C1 -C6 )烷基或-烷基(C0 -C6 )-Cy1 ， 或(R11 ，R11 ')成對取代基與攜載其的氮原子一起形成由5至7個環成員組成之芳族或非芳族環，其中除該氮原子以外可再含有1至3個選自氧、硫及氮之雜原子，應理解所討論的氮可經表示氫原子或直鏈或分支鏈(C1 -C6 )烷基之基團取代，且應理解可能的取代基之一或多個碳原子可經氘化， ¨ R12 表示-Cy5 、-Cy5 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy6 、-Cy5 -烷基(C0 -C6 )-O-烷基(C0 -C6 )-Cy6 、-Cy5 -烷基(C0 -C6 )-NR11 -烷基(C0 -C6 )-Cy6 、 -Cy5 -Cy6 -O-烷基(C0 -C6 )-Cy7 、-C(O)-NR11 R11 '、-NR11 R11 '、-OR11 、 -NR11 -C(O)-R11 '、-O-烷基(C1 -C6 )-OR11 、-SO2 -R11 、-C(O)-OR11 或-NH-C(O)-NH-R11 ， ¨ R13 、R13 '、R14 及R14 '彼此獨立地表示氫原子或視情況經取代之直鏈或分支鏈(C1 -C6 )烷基， ¨ R25 表示氫原子、羥基或羥基(C1 -C6 )烷基， ¨ Cy1 、Cy2 、Cy3 、Cy5 、Cy6 、Cy7 及Cy8 彼此獨立地表示環烷基、雜環烷基、芳基或雜芳基， ¨ n為等於0或1之整數， 應理解： - 「芳基」意指苯基、萘基、聯苯基、茚滿基或茚基， - 「雜芳基」意指任何由5至10個環成員組成之單環或雙環基團，其具有至少一個芳族部分且含有1至3個選自氧、硫及氮之雜原子， - 「環烷基」意指任何含有3至10個環成員之單環或雙環非芳族碳環基， - 「雜環烷基」意指任何含有3至10個環成員且含有1至3個選自氧、硫及氮之雜原子的單環或雙環非芳族碳環基，其可包括稠環、橋環或螺環系， 如此定義之芳基、雜芳基、環烷基及雜環烷基以及烷基、烯基、炔基、烷氧基可能經1至4個選自以下之基團取代：視情況經取代之直鏈或分支鏈(C1 -C6 )烷基、視情況經取代之直鏈或分支鏈(C2 -C6 )烯基、視情況經取代之直鏈或分支鏈(C2 -C6 )炔基、視情況經取代之直鏈或分支鏈(C1 -C6 )烷氧基、視情況經取代之(C1 -C6 )烷基-S-、羥基、側氧基(或適當時，N -氧化物)、硝基、氰基、-C(O)-OR'、-O-C(O)-R'、-C(O)-NR'R''、-NR'R''、-(C=NR')-OR''、直鏈或分支鏈(C1 -C6 )多鹵烷基、三氟甲氧基或鹵素，應理解，R'及R''彼此獨立地表示氫原子或視情況經取代之直鏈或分支鏈(C1 -C6 )烷基，且應理解，前述可能的取代基之一或多個碳原子可經氘化， 或其對映異構體、非對映異構體或滯轉異構體，或其與醫藥學上可接受之酸或鹼之加成鹽， 及(b)紫杉烷化合物， 用於同時、依序或分開使用。 E3.根據E1或E2之組合，其中紫杉烷化合物為太平洋紫杉醇或多西他賽。 E4.根據E1或E2之組合，其中MCL-1抑制劑為(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(5-氟呋喃-2-基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[1-(2,2,2-三氟乙基)-1H -吡唑-5-基]甲氧基}苯基)丙酸。 E5.根據E1或E2之組合，其中MCL-1抑制劑為(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸。 E6.根據E1或E2之組合，其中紫杉烷化合物為太平洋紫杉醇。 E7.根據E1或E2之組合，其中紫杉烷化合物為多西他賽。 E8.根據E1或E2之組合，其中MCL-1抑制劑為(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸且紫杉烷化合物為太平洋紫杉醇。 E9.根據E1或E2之組合，其中MCL-1抑制劑為(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(5-氟呋喃-2-基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[1-(2,2,2-三氟乙基)-1H -吡唑-5-基]甲氧基}苯基)丙酸且紫杉烷化合物為太平洋紫杉醇。 E10.根據E1或E2之組合，其中MCL-1抑制劑為(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸且紫杉烷化合物為多西他賽。 E11.根據E1或E2之組合，其中MCL-1抑制劑為(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(5-氟呋喃-2-基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[1-(2,2,2-三氟乙基)-1H -吡唑-5-基]甲氧基}苯基)丙酸且紫杉烷化合物為多西他賽。 E12.根據E5之組合，其中在組合治療期間(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸之劑量為25 mg至1500 mg。 E13.根據E5或E12之組合，其中在組合治療期間投與(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸一週一次。 E14.根據E1至E13中之任一者之組合，其中MCL-1抑制劑經口投與且紫杉烷化合物經靜脈內投與。 E15. 根據E1至E13中之任一者之組合，其中MCL-1抑制劑及紫杉烷化合物經靜脈內投與。 E16.根據E1至E15中之任一者之組合，其用於治療癌症。 E17.根據E16之組合，其中MCL-1抑制劑及紫杉烷化合物以對癌症治療共同治療有效的量提供。 E18.根據E16之組合，其中MCL-1抑制劑及紫杉烷化合物以對癌症治療協同有效的量提供。 E19. 根據E16之組合，其中MCL-1抑制劑及紫杉烷化合物以能夠使得癌症治療中各化合物之所需劑量減少的協同有效量提供，同時提供有效的癌症治療，且最終降低副作用。 E20.根據E16至E19中之任一者之組合，其中癌症為乳癌。 E21.根據E20之組合，其中癌症為三陰性乳癌，尤其化學抗性的三陰性乳癌，更特定而言，對紫杉烷療法有抗性之三陰性乳癌。 E22.根據E16至E19中之任一者之組合，其中癌症為肺癌，尤其非小細胞肺癌或小細胞肺癌。 E23.根據E1至E15中之任一者之組合，其進一步包含一或多種賦形劑。 E24.包含根據E1至E15中之任一者之組合的醫藥組合物，其與一或多種醫藥學上可接受之賦形劑組合。 E25.根據E24之醫藥組合物，其用於治療癌症。 E26.根據E25之醫藥組合物，其中癌症為乳癌。 E27.根據E26之醫藥組合物，其中癌症為三陰性乳癌，尤其化學抗性的三陰性乳癌，更特定而言，對紫杉烷療法有抗性之三陰性乳癌。 E28.根據E25之醫藥組合物組合，其中癌症為肺癌，尤其非小細胞肺癌或小細胞肺癌。 E29.根據E1至E15中之任一者之組合在製造用於治療癌症之藥物中的用途。 E30.根據E29之用途，其中癌症為乳癌。 E31.根據E30之用途，其中癌症為三陰性乳癌，尤其化學抗性的三陰性乳癌，更特定而言，對紫杉烷療法有抗性之三陰性乳癌。 E32.根據E29之用途，其中癌症為肺癌，尤其非小細胞肺癌或小細胞肺癌。 E33.一種藥物，其分開包含或一起包含， (a)如E1中所定義之式(I)之MCL-1抑制劑，及 (b)紫杉烷化合物， 用於同時、依序或分開投與，且其中MCL-1抑制劑及紫杉烷化合物以治療癌症之有效量提供。 E34.一種藥物，其分開包含或一起包含， (a)如E2中所定義之式(II)之MCL-1抑制劑，及 (b)紫杉烷化合物， 用於同時、依序或分開投與，且其中MCL-1抑制劑及紫杉烷化合物以治療癌症之有效量提供。 E35.一種治療癌症之方法，其包含向對其有需要之個體投與共同治療有效量之以下各者： (a)如E1中所定義之式(I)之MCL-1抑制劑，及 (b)紫杉烷化合物。 E36.一種治療癌症之方法，其包含向對其有需要之個體投與共同治療有效量之以下各者： (a)如E2中所定義之式(II)之MCL-1抑制劑，及 (b)紫杉烷化合物。 E37.一種用於使(i)難以用至少一種化學療法治療或(ii)用化學療法治療之後復發或(i)及(ii)兩者之患者敏感的方法，其中該方法包含向該患者投與共同治療有效量之如E1中所定義之式(I)之MCL-1抑制劑與如本文中所描述之紫杉烷化合物。 E38.一種用於使(i)難以用至少一種化學療法治療或(ii)用化學療法治療之後復發或(i)及(ii)兩者之患者敏感的方法，其中該方法包含向該患者投與共同治療有效量之如E2中所定義之式(II)之MCL-1抑制劑與如本文中所描述之紫杉烷化合物。 「組合」係指在一個單位劑型(例如膠囊、錠劑或藥囊)中之固定劑量組合、非固定劑量組合、或用於組合投與之部件之套組，其中本發明之化合物及可一或多種組合搭配物(例如如下文所解釋之另一藥物，亦稱為「治療劑」或「併用製劑」)同時間獨立地投與，或在時間間隔內分開投與，尤其其中此等時間間隔使得組合搭配物展現合作(例如協同)之作用。 如本文中所用之術語「共同投與」或「組合投與」或其類似術語意欲涵蓋向有需要之單一個體(例如患者)投與所選擇之組合搭配物，且意欲包括其中製劑不一定藉由相同投與途徑投與或同時投與之治療方案。 術語「固定劑量組合」意指將活性成分(例如式(I)之化合物)及一或多種組合搭配物二者成為一個實體或劑量之形式同時投與患者。 術語「非固定劑量組合」意指將活性成分(例如本發明之化合物)及一或多種組合搭配物，呈分開實體或劑量，在沒有特定時間限制下同時或依序投與患者，其中此類投藥法在患者體內提供兩種化合物之治療有效量。後者亦適用於混合物療法，例如投與三種或更多種活性成分。 「癌症」意指其中一群細胞呈現失控生長之一類疾病。癌症類型包括實體腫瘤，包括癌瘤、肉瘤或母細胞瘤。特定言之，「癌症」係指乳癌及肺癌。 術語「共同治療有效」意指治療劑可依其偏好的時間間隔(依錯開時間順序的方式，尤其依特定順序方式)分開投與待治療之溫血動物，尤其人類，而仍顯示(較佳協同的)相互作用(共同治療效果)。此情況可特別藉由追蹤血液含量來確定，顯示兩種化合物至少在某些時間間隔期間同時存在於待治療之人類之血液中。 「協同有效」或「協同」意指在投與兩種或更多種藥劑之後所觀測到之治療效果大於投與各單一藥劑之後所觀測到之總治療效果。 如本文中所使用，術語「治療(treat、treating或treatment)」任何疾病或病症在一個實施例中係指改善疾病或病症(亦即，減緩或遏制或減少疾病或其臨床症狀中之至少一者之發展)。在另一實施例中，「治療(treat、treating或treatment」係指緩解或改善至少一種身體參數，包括患者可能辨別不出之身體參數。在又一實施例中，「治療(treat、treating或treatment)」係指在身體上(例如穩定可辨別的症狀)、生理上(例如穩定身體參數)或在身體上及生理上調節疾病或病症。 如本文中所使用，若個體將在生物學上、醫學上或生活品質上受益於治療，則該個體「需要」此治療。 在另一態樣中，提供一種用於使(i)難以用至少一種化學療法治療或(ii)用化學療法治療之後復發或(i)及(ii)兩者之患者敏感的方法，其中該方法包含向患者投與式(I)或式(II)之MCL-1抑制劑與如本文中所描述之紫杉烷化合物。經致敏的患者係對涉及投與式(I)或式(II)之MCL-1抑制劑與如本文中所描述之紫杉烷化合物之治療起反應或對此治療尚未發展出抗性的患者。 「藥物」意指醫藥組合物或幾種醫藥組合物之組合，其含有在一或多種賦形劑存在下之一或多種活性成分。 在根據本發明之醫藥組合物中，活性成分的重量比例(活性成分之重量比組合物之總重量)為5%至50%。 在根據本發明之醫藥組合物中，更尤其將使用適於經口、非經腸且尤其靜脈內、全皮膚或反皮膚、鼻、直腸、經舌、眼或呼吸道投與的彼等物，更確切而言，錠劑、糖衣丸劑、舌下錠劑、硬明膠膠囊、直腸給藥劑型、膠囊、口含錠、可注射製劑、噴霧劑、眼或鼻滴劑、栓劑、乳膏、軟膏、經皮凝膠等。 根據本發明之醫藥組合物包含一或多種醫藥學上可接受之賦形劑或載劑，其選自稀釋劑、潤滑劑、黏合劑、崩解劑、穩定劑、防腐劑、吸附劑、著色劑、甜味劑、調味劑等。藉助於非限制性實例，可提及： w作為稀釋劑：乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、纖維素、甘油， w 作為潤滑劑：二氧化矽、滑石、硬脂酸及其鎂鹽及鈣鹽、聚乙二醇， w 作為黏合劑：矽酸鎂鋁、澱粉、明膠、黃蓍、甲基纖維素、羧甲基纖維素鈉及聚乙烯吡咯啶酮， w 作為崩解劑：瓊脂、褐藻酸及其鈉鹽、起泡性混合物。 組合之化合物可同時或依序投與。投與途徑較佳為靜脈內輸注或注射，且對應的醫藥組合物可實現活性成分之瞬時或延遲釋放。組合之化合物此外可以各自含有活性成分中之一者的兩個單獨醫藥組合物之形式投與，或以活性成分呈混雜物形式之單個醫藥組合物之形式投與。 可用的給藥方案根據患者之性別、年齡及重量；投與途徑；癌症及任何相關治療之性質而變化，且在每週25 mg至1500 mg、更佳每週50 mg至1400 mg MCL-1抑制劑之範圍內。紫杉烷化合物之劑量將與其獨自投與時相同。藥理學資料 實例 1: 在乳癌及肺癌細胞株中組合 MCL - 1 抑制劑 ( 化合物 1 ) 與 太平洋紫杉醇對增殖之活體外作用 在19種乳癌細胞株(BT-20、BT-474、BT-549、Cal-148、HCC1143、HCC1395、HCC1500、HCC1937、HCC1954、HCC38、HCC70、Hs 578T、MCF7、MDA-MB-157、MDA-MB-231、MDA-MB-436、MDA-MB-453、MDA-MB-468及SK-BR-3)及3種肺癌細胞株(H522、H23及A549)之圖中評估組合MCL-1抑制劑(化合物1)與太平洋紫杉醇對增殖之作用。 材料及方法 將化合物以10 mM之原料濃度溶解在100% DMSO (Sigma，目錄號#D2438-50ML)中且在-20℃下儲存直至使用。將化合物在2 ml深96孔盤(Greiner bio-one，目錄號780271)中排列，連續稀釋3倍。化合物1以0.0至10.0 μM範圍內之濃度使用。太平洋紫杉醇在乳癌細胞中以0.0至1.0 μM範圍內之濃度且在肺癌細胞中以0.0至2.0 μM範圍內之濃度使用。 所有細胞株均購自美國菌種保存中心(American Type Culture Collection)且根據供應商建議培養。所有細胞株均用10% FBS(GIBCO，目錄號10099-141)補充。所有細胞株均藉由以Idexx Radil (Columbia，MO，USA)進行之PCR偵測分析確定不含黴漿菌污染且藉由SNP分析驗證。自冷凍原料解凍細胞，經由≥1傳代擴增且在37℃下在5% CO2 中生長。將細胞擴增至T-75燒瓶中且在接種之前使用Beckman-Coulter ViCell計數器評估活力。為分離且擴展細胞株，使用0.25%胰蛋白酶-EDTA (Corning Costar，目錄號#25-053-CL)將細胞自燒瓶移出。 以72小時CellTiter-GloTM (CTG)分析來量測細胞增殖且展示的所有結果均為至少一式三份量測之結果。以80 μL培養基之最終體積及每孔3000細胞之密度將細胞分配至經組織培養處理之96孔盤(Costar，目錄號3904)。在接種16至24小時之後，將20 μL之各化合物稀釋系列轉移至含有細胞之盤中，引起上述化合物濃度範圍及0.16%之最終DMSO濃度。另外，如下文所描述，使用CellTiter-Glo®發光細胞活力分析來分析第零天盤。在72小時之化合物治療之後使用CellTiter-Glo™發光細胞活力分析(Promega，目錄號#G7573)測定化合物對細胞增殖之作用。此係基於定量所存在的ATP (其表明代謝活性細胞之存在)來測定培養物中活細胞之數目的均質方法。方法詳細描述於Technical Bulletin, TB288 Promega中。簡言之，向盤中添加100 μl CTG反應劑，且將盤在定軌振盪器上培育20至30分鐘。隨後將盤在Perkin Elmer VictorTM X4讀盤器上讀數。 使用組合模組(Combo Module)軟體使用洛伊協同模型計算生長抑制百分比、過量抑制及生長抑制(如在Lehar等人，Nature Biotechnology 2009, 27(7), 659-66中所描述)，該洛伊協同模型度量若兩個藥物表現為劑量相加方式則應預期對高於什麼程度之生長之作用。正數表示增加協同之區域。相對於DMSO之生長抑制百分比在標記為“抑制 ”之圖中展示。超出預期量之抑制之量在標記為“洛伊過量抑制 ”之圖中。正規化至第零天之抑制之量在標記為“生長抑制 ”之圖中展示。化合物1之濃度沿底部列由左至右展示且太平洋紫杉醇之增加濃度沿最左邊欄由下至上展示。網格中之所有其餘點展示來自對應於在兩個軸上表示之單一藥劑濃度的兩種抑制劑的組合的結果。藉由尋找計算曲線超過50%活性標記之化合物濃度來確定絕對IC50 。在組合模組軟體中計算絕對IC50 及協同得分，如在Lehar等人2009中所描述。協同得分 SS ~ 0 → 劑量相加 SS ＞2 → 協同 SS ＞1 → 弱協同表 1. 指示各化合物之單一藥劑絕對IC50 值及化合物1與太平洋紫杉醇之組合之協同得分量測。當觀測到得分≥2.0時，相互作用視為協同。 結果 化合物1作為單一藥劑抑制7/19乳癌細胞株及2/3肺癌細胞株之生長，IC50 低於1000 nM (表1)。 太平洋紫杉醇作為單一藥劑抑制17/19乳癌細胞株及3/3肺癌細胞株之生長，IC50 低於1000 nM。 在組合中，化合物1與太平洋紫杉醇治療在16/19乳癌細胞株及3/3肺癌細胞株中引起協同生長抑制(亦即協同得分高於2 (Lehar等人，2009))(表1)。在11種細胞株中協同作用明顯，協同得分高於6。重要地，協同不依賴於單一藥劑抗增殖作用，且協同作用跨大範圍之單一藥劑濃度出現(圖1、圖2及圖3)，其應證實就關於給藥水準及方案之靈活性而言活體內有利。實例 2 ： 在乳癌及肺癌細胞株中組合 MCL - 1 抑制劑 ( 化合物 2 ) 與太平洋紫杉醇對增殖之活體外作用 在2種乳癌細胞株(MDA-MB-453及MDA-MB-468)及一種肺癌細胞株(H522)之圖中評估組合MCL-1抑制劑(化合物2)與太平洋紫杉醇對增殖之作用。 材料及方法 獲得細胞株且保持在如表2中所指示之補充有胎牛血清的基礎培養基中。另外，所有培養基均含有青黴素(100 IU/ml)、鏈黴素(100 µg/ml)及L-麩醯胺酸(2 mM)。 將細胞株在37℃下在含有5% CO2 之潮濕氣氛中培養且在T-150燒瓶中擴增。在所有情況中自冷凍原料解凍細胞，使用適當稀釋液經由≥1代擴增，使用CASY細胞計數器計數且評估活力，隨後以如表2中所指示之密度接種150微升/孔至96孔盤中。所有細胞株均確定為內部無黴漿菌污染。 以於DMSO中之5 mM之濃度製備化合物之儲備溶液且於-20℃下儲存。 為了分析在單一藥劑中或在組合中之化合物之活性，接種細胞且用各經分配的化合物之七個或八個3.16倍連續稀釋液個別地或以棋盤格形式中之所有可能排列之方式直接處理至細胞分析盤中，如圖5及圖6中所指示。在培育3天之後，評估單一藥劑以及其棋盤格組合對細胞活力的影響，該分析在37℃/5% CO2 下藉由使用CellTiterGlo以75 μL反應劑/孔定量細胞ATP水準來進行。進行至少兩個獨立實驗，各一式兩份進行。在多用途讀盤器上定量發光。 使用標準四參數曲線擬合計算單一藥劑IC50 。化合物組合之間潛在的協同相互作用使用過量抑制2D矩陣根據洛伊相加模型進行評估且作為協同得分報告(Lehar等人2009)。所有計算使用可在Horizon網站獲得之ChaliceTM 生物資訊(Bioinformatics)軟體來進行。 表2中所指示之倍增時間為自細胞解凍至其在96孔盤中接種所進行之不同傳代(在T-150燒瓶中)中所獲得的倍增時間的平均值。協同得分 SS ~ 0 →相加 SS ＞1 →若弱協同 SS ＞2 →協同表 2. 用於組合實驗之細胞株之身分標識及分析條件。 表 3. 指示化合物2及太平洋紫杉醇之單一藥劑IC50 值。化合物在3天期間與細胞一起培育。 表 4. 指示化合物2及太平洋紫杉醇組合之協同得分。當觀測到之得分≥2.0時，認為相互作用為協同的。指示化合物之起始濃度、最大抑制之平均值及協同得分之標準差(sd)。化合物在3天期間與細胞一起培育。 結果 化合物2作為單一藥劑抑制1/3所測試的細胞株之生長，且H522細胞株之IC50 為140 nM (表3)。 太平洋紫杉醇作為單一藥劑抑制2/3所測試的細胞株之生長，且IC50 低於1 nM。 在三種所測試的細胞株中，以組合形式之化合物2及太平洋紫杉醇處理引起協同生長抑制(亦即協同得分高於2 (Lehar等人2009))(表4)。在2種細胞株中協同作用明顯，協同得分6.5及16.9。重要地，協同不依賴於單一藥劑抗增殖作用，且協同作用跨大範圍之單一藥劑濃度出現(圖4及圖5)，其應證實就關於給藥水準及方案之靈活性而言活體內有利。實例 3 ： 活體外 MCL - 1 抑制劑與多西他賽之間之協同 吾人研究MCL-1抑制劑(化合物2)是否與目前用於TNBC治療中之藥劑引發協同活性。在SK-BR-3細胞中將化合物2與多西他賽組合。 材料及方法 細胞株 ： 將乳癌細胞株SK-BR-3在補充有10%胎牛血清(fetal calf serum，FCS)及10 µg/ml胰島素之RPMI-1640加GlutaMAX-1 (Gibco)中保持。用於活力分析，在96孔盤中將細胞以2×105 個細胞/毫升接種在補充有10% FCS及10 μg/ml胰島素之RPMI-1640培養基(Gibco)中，且用增大濃度之化合物2處理。 細胞活性 ：根據製造商說明書使用細胞滴定Glo發光分析(Cell Titer Glo Luminescent Assay)(Promega)評估細胞活力。以10 μM使用廣譜凋亡蛋白酶抑制劑QVD-OPh水合物(Sigma-Aldrich)。藉由流式細胞測量術分析碘化丙錠排斥(5 μg/ml)。為了活體外細胞分析以解決不同藥物之間之協同，使用Bliss獨立性方法(Prichard等人，Antimicrobial Agents and Chemotherapy 1991, 35, 1060-5)測定組合作用。 結果 多西他賽及MCL-1抑制劑在兩種組分之極低濃度下顯示明顯協同。特定言之，多西他賽及化合物2在多西他賽(2 nM)及化合物2 (31 nM)之極低濃度下顯示明顯協同(圖6及圖7)。凋亡蛋白酶與泛凋亡蛋白酶(pan-caspase)抑制劑QVD-OPH之抑制有效阻斷細胞死亡，證實細胞死亡係由細胞凋亡觸發(圖6)。實例 4 ： 活體內 MCL - 1 抑制使 PDX 腫瘤對紫杉烷治療敏感 因為活體外分析揭示在組合療法中乳癌細胞株對化合物2敏感，吾人接下來在代表三種TNBC (110T、838T及PDX OD-BRE-0589)之三個PDX模型中測定其活體內治療效果。 材料及方法 人類乳癌組織經由皇家墨爾本醫院組織庫(Royal Melbourne Hospital Tissue Bank)、Victorian Cancer Biobank及Georges-Francois Leclerc Center在相關機構審查委員會批准下獲自同意患者。人類倫理批准獲自沃爾特和伊莉莎霍爾學院(Walter and Eliza Hall Institute，WEHI)人類研究倫理委員會及Georges-Francois Leclerc Center人類研究倫理委員會。根據機構指南培育且維護NOD SCID IL2 γ受體基因剔除小鼠或SCID小鼠。所有動物實驗經WEHI及施維雅研究機構(Servier Research Institute，IdRS)動物倫理委員會批准。 每週靜脈內注射化合物2 (25 mg/kg)或其媒劑持續六週。將化合物2溶解在20% (2-羥基丙基)-β-環糊精及25 mM鹽酸中。如先前所描述製備多西他賽(10 mg/kg腹膜內)或其媒劑(Oakes等人，Proceedings of the National Academy of Sciences of the USA 2012, 109, 2766-71)且在化合物2之前一天每週腹膜內注射。每週三次監測小鼠之腫瘤發展且使用電子游標測徑規來量測腫瘤尺寸。藉由量測最小及最大腫瘤直徑使用式：(最小直徑)2 (最大直徑)/2來估算腫瘤體積。腫瘤一出現，便將小鼠隨機化成處理組。當腫瘤體積達到80至120 mm3 時開始處理。使用Study Director軟體(v 3.0，studylog)管理隨機化及腫瘤量測。在腫瘤體積超出600 mm3 之第一次量測或出現並非由於疾病進展或藥物毒性導致之動物健康惡化(小鼠經檢查)時處死小鼠。 結果 化合物2單獨不足以抑制腫瘤生長。然而，在三個PDX模型中吾人觀測到，相比於多西他賽作為單一藥劑投與，與多西他賽組合具有優良活性，引起動物存活率顯著提高(圖8)。 此等結果表明，與紫杉烷化合物組合之MCL-1抑制劑可能顯著提高腫瘤反應及臨床結果。實例 5 ：與多西他賽組合之 MCL - 1 抑制劑活體內具有良好耐受性 將NOD SCID IL2 γ受體基因剔除小鼠用多西他賽(15 mg/kg，腹膜內一次)及25 mg/kg或50 mg/kg之化合物2 (每組3隻小鼠，靜脈內注射，每週一次持續3週)處理。每週三次監測其體重持續3週。 與多西他賽組合之化合物2良好耐受且不引發顯著體重損失(圖9)。實例 6 ：與太平洋紫杉醇組合之化合物 1 在裸大鼠之 MDA - MB - 231 乳異種移植模型中之功效 方法 此研究評估在雌性NTac:NIH-Whn裸大鼠(Taconic)之三陰性乳癌(TNBC)模型MDA-MB-231中與太平洋紫杉醇組合之化合物1之抗腫瘤活性及耐受性。 在此等研究中使用化合物1 (free base)及太平洋紫杉醇(Sandoz)。按照製造商之說明書用無菌5% (w/v)葡萄糖溶液稀釋太平洋紫杉醇至1.5 mg/ml，用以按5 ml/kg劑量體積以7.5 mg/kg投與[在5%(w/v)葡萄糖溶液中最終乙醇與十六醇聚氧乙烯醚EL濃度分別為10%與15%]。在脂質調配物(Novartis)中以5 mg/ml調配化合物1，用以按10 ml/kg劑量體積以50 mg/kg劑量投與。 三陰性乳癌細胞株MDA-MB-231獲自ATCC細胞庫。在37℃下在空氣中之5% CO2 氣氛中，在補充有10% FCS (BioConcept Ltd. Amimed，# 2-01F36-I)及4 mML-麩醯胺酸(BioConcept Ltd. Amimed，#5-10K00-H)之DMEM高葡萄糖培養基(BioConcept Ltd. Amimed)中培養細胞。為確立MDA-MB-231，收集異種移植細胞且再懸浮於HBSS (Gibco，#14175)中且在經異氟醚麻醉的動物經右腹皮下注射含有1×107 細胞之200 µL之前與基質膠(Matrigel) (BD Bioscience，#354234) (1:1 v/v)混合。在細胞接種之前的二十四小時，所有動物皆使用γ照射器用5Gy照射超過2分鐘。 細胞接種後定期監測腫瘤生長，且將動物隨機化成處理組(n=7至8)，平均腫瘤體積約400 mm3 。各組用以下處理： 1)用於調配太平洋紫杉醇之媒劑靜脈內加脂質媒劑靜脈內；或 2) 7.5 mg/kg靜脈內推注太平洋紫杉醇加脂質媒劑靜脈內；或 3)用於調配太平洋紫杉醇之媒劑靜脈內加50 mg/kg靜脈內之化合物1；或 4) 7.5 mg/kg靜脈內太平洋紫杉醇加50 mg/kg靜脈內化合物1。 用於太平洋紫杉醇之媒劑或太平洋紫杉醇作為經由尾側靜脈之0.5小時或16小時之緩慢推注劑量一週一次(QW)投與，之後脂質調配物中之化合物1之媒劑或化合物1本身藉由在尾側靜脈中靜脈內輸注15分鐘投與。用於推注投與及15分鐘輸注，分別將動物用異氟醚/O2 麻醉約5及25分鐘。 腫瘤體積使用測徑規每週2至3次來量測。由(L×W2 ×π/6)計算以mm3 為單位之腫瘤尺寸，其中W=腫瘤之寬度且L=腫瘤之長度。亦將動物每週稱重2至3次，且針對任何不利影響之明顯跡象進行頻繁檢測。 腫瘤及體重變化資料使用GraphPad Prism 7.00 (GraphPad Software)進行統計分析。若資料中之變動為正常分佈，則資料使用藉由事後鄧尼特測試之單因素變異數分析(one-way ANOVA)來分析，用於處理組與對照組之比較。事後杜凱氏測試(post hoc Tukey's test)用於組內比較。否則，使用Kruskal-Wallis分級測試事後鄧尼特。適當時，結果呈現為平均值±SEM。 作為功效之量度，T/C%值在實驗結束時根據下式計算： (Δ腫瘤體積處理 /Δ腫瘤體積對照 )*100 腫瘤消退根據下式計算： -(Δ腫瘤體積處理 /腫瘤體積處理開始 )*100 其中Δ腫瘤體積表示評估日之平均腫瘤體積減去實驗開始時之平均腫瘤體積。 結果：功效及耐受性 在太平洋紫杉醇之媒劑[乙醇:十六醇聚氧乙烯醚EL:5% (w/v)葡萄糖(10%:15%:75%)]之後以50 mg/kg給藥化合物1 0.5小時或16小時具有良好耐受性。 在QW×7靜脈內輸注投與之後，脂質調配物中之化合物1 (50 mg/kg QW)在MDA-MB-231異種移植模型中不展現功效(圖10及圖12)。 太平洋紫杉醇7.5 mg/kg引起腫瘤生長延遲(T/C%=34%)且與媒劑處理組顯著不同(p＜0.05)(圖10及圖12)。 相隔0.5小時或16小時投與之7.5 mg/kg靜脈內太平洋紫杉醇加50 mg/kg靜脈內化合物1的組合在開始處理之後第28天在存活動物(在兩個組中均為3/8)中分別引起82%與59%消退 (圖10)。在開始處理之第46天，在存活動物2/8及3/8中腫瘤消退分別為92%與81%。在第28天及第46天，來自兩個此等組合組之動物中之腫瘤體積顯著不同(p＜0.05)於來自用太平洋紫杉醇或化合物1單獨處理之動物中之腫瘤體積(圖10)。 相隔16小時投與之7.5 mg/kg靜脈內太平洋紫杉醇加25 mg/kg靜脈內化合物1之組合在存活(7/7)動物中引起腫瘤停滯(在開始處理之後第28天15%消退且在第49天T/C%值為2%)(圖12)。根據體重變化及臨床跡象，此劑量方案具有良好耐受性。 相隔16小時投與之3.75 mg/kg靜脈內太平洋紫杉醇加50 mg/kg靜脈內化合物1之組合在存活(7/7)動物中引起腫瘤停滯至第35天(在開始處理之後第28天3%消退且在第49天T/C%值為20%)(圖12)。根據體重變化及臨床跡象，此劑量方案具有良好耐受性(圖11及圖13)。此等資料表明，太平洋紫杉醇與化合物1之組合，相比於其中任一藥劑單獨，在抗腫瘤活性上具有明顯積極影響。實例 7 ： 活體內 MCL - 1 抑制使 PDX 腫瘤對紫杉烷治療敏感 吾人測定組合療法中之化合物1在TNBC 110T PDX模型中之活體內治療效果。 材料及方法 人類乳癌組織經由皇家墨爾本醫院組織庫、Victorian Cancer Biobank及Georges-Francois Leclerc Center在相關機構審查委員會批准下獲自同意患者。人類倫理批准獲自沃爾特和伊莉莎霍爾學院(WEHI)人類研究倫理委員會及Georges-Francois Leclerc Center人類研究倫理委員會。根據機構指南培育且維護NOD SCID IL2 γ受體基因剔除小鼠或SCID小鼠。所有動物實驗經WEHI及施維雅研究機構(IdRS)動物倫理委員會批准。 將一群40雌性NSG小鼠用早期傳代人類乳腫瘤(TNBC PDX110)之解凍的單細胞懸浮液接種。簡言之，將100,000細胞再懸浮在以3:1之比率之10 µl移植緩衝液(50%胎牛血清、10%之0.04%錐蟲藍溶液及40% PBS)與生長因子降低基質膠[BD]中，且注射至3或4週齡NOD-SCID-IL2Rγc -/- 雌性小鼠之清除的乳腺脂肪墊中。每週三次監測小鼠之腫瘤發展且使用電子游標測徑規來量測腫瘤尺寸。藉由量測最小及最大腫瘤直徑使用式：(最小直徑)2 (最大直徑)/2來估算腫瘤體積。腫瘤一旦達到60至110 mm3 體積便將小鼠隨機化成處理組且開始處理。藉由用PBS溶解儲備溶液(20 mg/ml)製備多西他賽或其媒劑且每21第天腹膜內注射持續兩個治療週期。療法之持續時間由條形指示。將化合物1溶解於20% (2-羥基丙基)-β - 環糊精及25 mM鹽酸中。每週兩次靜脈內注射化合物1 (15 mg/kg)或其媒劑持續六週。在腫瘤體積超出600 mm3 之第一次量測或由於疾病進展或藥物毒性之外的原因導致的動物健康惡化(經檢查事件)時處死小鼠。每處理組n=9至10隻小鼠。 結果 化合物1單獨不足以抑制腫瘤生長。然而，在PDX模型中吾人觀測到，相比於多西他賽作為單一藥劑投與，與多西他賽組合具有優良活性，引起動物存活率顯著提高(圖14)。 此等結果表明，與紫杉烷化合物組合之MCL-1抑制劑可能顯著提高腫瘤反應及臨床結果。實例 8 ：在攜帶患者衍生 TNBC 模型之雌性 SCID 小鼠中多西他賽及化合物 1 之抗腫瘤活性 此研究評估在雌性SCID小鼠中在TNBC PDX模型OD-BRE-00589中化合物1組合多西他賽之抗腫瘤活性。 方法 在5%乙醇、5% PS80及90%葡萄糖中以0.67 mg/ml調配多西他賽用於10 mg/kg投與。在脂質調配物(Novartis)中以7.5 mg/ml調配化合物1用於70 mg/kg投與。 OD-BRE-00589係三陰性乳癌PDX，獲自IMODI聯盟。同意患者獲自Georges-Francois Leclerc Center人類研究倫理委員會。其移植在SCID小鼠上作為27 mm3 體積之片段。 片段移植之後定期監測腫瘤生長且在移植之後第11天將動物隨機化成平均腫瘤體積為約200 mm3 之處理組(n=8)。對照組不做處理且另一組用以下處理： 1) 70 mg/kg化合物1靜脈內，或 2) 10 mg/kg多西他賽靜脈內，或 3) 10 mg/kg多西他賽靜脈內，接著30分鐘後用70 mg/kg化合物1，或 4) 10 mg/kg多西他賽靜脈內，接著72小時後用70 mg/kg化合物1。 在尾側靜脈中進行一次投藥。 腫瘤體積使用測徑規每週2至3次來量測。腫瘤體積使用式：長度×寬度2 /2計算。亦將動物每週稱重2至3次，且針對任何不利影響之明顯跡象進行頻繁檢測。 結果 化合物1單獨不足以抑制腫瘤生長。然而，在PDX模型中吾人觀測到，相比於多西他賽作為單一藥劑投與，與多西他賽組合具有優良活性，引起抗腫瘤活性顯著提高(圖15)。 此等結果表明，與紫杉烷化合物組合之MCL-1抑制劑可能顯著提高腫瘤反應及臨床結果。實例 9 ：在對多西他賽具有抗性之 PDX 模型 中與太平洋紫杉醇組合之化合物 1 之功效研究 方法 測試已證實活體內對多西他賽具有抗性的PDX模型。各處理組包括5隻雌性瑞士裸鼠，年齡為6至8週齡。當異種移植物達到平均腫瘤體積為約120至150 mm3 時開始處理。隨後幾組小鼠隨機受不同處理之影響。經移植動物之數目視腫瘤生長之同質性而定。 在脂質調配物中調配，化合物1以一週一次70 mg/kg靜脈內投與。調配物必須臨時地製備。在0.9% NaCl中稀釋之太平洋紫杉醇以25 mg/kg腹膜內給予。在投與化合物1之前給予太平洋紫杉醇QW 16小時。不同處理之投藥方案定義為如下： 一週兩次量測腫瘤尺寸且一週一次量測個別小鼠之重量。直至大多數反應組之中值腫瘤體積開始再次生長，處理完成。在終止處理之後在各組之間比較小鼠達到復發之時間。使用Statview軟體，比較腫瘤體積和/或相對腫瘤體積(relative tumor volume，RTV，屆時體積除以第1天時之初始體積之比率乘以100)、處理組中之最佳化生長抑制(RTV之比率(×100))除以對照中之RTV)、生長延遲(在處理組及對照組中200 mm3 初始腫瘤體積4倍擴增所必需之天數)及體重變化。 在太平洋紫杉醇處理之後若觀測到復發，則用化合物1+太平洋紫杉醇組合再次攻擊腫瘤。此藉由以下來完成：在太平洋紫杉醇處理組中包括10隻小鼠且隨後用太平洋紫杉醇單獨處理腫瘤復發的小鼠(5隻動物)或以組合形式處理腫瘤復發的小鼠(5隻動物)，或藉由使用來自功效研究之非隨機化小鼠。若觀測到對太平洋紫杉醇之初始反應，則包括隨機化之後餘下之額外動物用於此研究。 結果 化合物1單獨不足以抑制腫瘤生長。然而，吾人觀測到相比於太平洋紫杉醇作為單一藥劑投與，與太平洋紫杉醇組合具有優良活性，在對紫杉烷化合物有抗性之PDX模型中引起抗腫瘤活性顯著提高。 此等結果表明，與紫杉烷化合物組合之MCL-1抑制劑可能顯著提高腫瘤反應及臨床結果。Therefore, the present invention provides a combination in Example E1, which comprises: (a) an MCL-1 inhibitor of formula (I):Where: ¨ D represents a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, ¨ E represents a furyl, thienyl or pyrrolyl ring, ¨ X1 , X3 , X4 And X5 Independently represent a carbon atom or a nitrogen atom, ¨ X2 C-R26 Group or nitrogen atom, ¨It means that the ring is aromatic, ¨ Y represents a nitrogen atom or C-R3 Group, ¨ Z represents a nitrogen atom or C-R4 Group, ¨ R1 Represents a halogen atom, straight or branched chain (C1 -C6 ) Alkyl, linear or branched (C2 -C6 ) Alkenyl, linear or branched (C2 -C6 ) Alkynyl, linear or branched (C1 -C6 ) Polyhaloalkyl, hydroxyl, hydroxyl (C1 -C6 ) Alkyl, linear or branched (C1 -C6 ) Alkoxy, -S- (C1 -C6 ) Alkyl, cyano, nitro, -Cy8 , -Alkyl (C0 -C6 ) -NR11 R11 ', -O-alkyl (C1 -C6 ) -NR11 R11 ', -O-alkyl (C1 -C6 ) -R12 , -C (O) -OR11 , -O-C (O) -R11 , -C (O) -NR11 R11 ', -NR11 -C (O) -R11 ', -NR11 -C (O) -OR11 ', -Alkyl (C1 -C6 ) -NR11 -C (O) -R11 ', -SO2 -NR11 R11 'Or -SO2 -Alkyl (C1 -C6 ), ¨ R2 , R3 , R4 And R5 Independently represent a hydrogen atom, a halogen atom, a straight chain or a branched chain (C1 -C6 ) Alkyl, linear or branched (C2 -C6 ) Alkenyl, linear or branched (C2 -C6 ) Alkynyl, linear or branched (C1 -C6 ) Polyhaloalkyl, hydroxyl, hydroxyl (C1 -C6 ) Alkyl, linear or branched (C1 -C6 ) Alkoxy, -S- (C1 -C6 ) Alkyl, cyano, nitro, -alkyl (C0 -C6 ) -NR11 R11 ', -O-Cy1 , -Alkyl (C0 -C6 ) -Cy1 , -Alkenyl (C2 -C6 ) -Cy1 , -Alkynyl (C2 -C6 ) -Cy1 , -O-alkyl (C1 -C6 ) -NR11 R11 ', -O-alkyl (C1 -C6 ) -R12 , -C (O) -OR11 , -O-C (O) -R11 , -C (O) -NR11 R11 ', -NR11 -C (O) -R11 ', -NR11 -C (O) -OR11 ', -Alkyl (C1 -C6 ) -NR11 -C (O) -R11 ', -SO2 -NR11 R11 'Or -SO2 -Alkyl (C1 -C6 ), Or (R1 , R2 ), (R2 , R3 ), (R3 , R4 ), (R4 , R5 ) A pair of substituents together with the carbon atom carrying it forms an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. It is understood that the resulting ring may be substituted with 1 to 2 groups selected from halogen, linear or branched (C1 -C6 ) Alkyl, -alkyl (C0 -C6 ) -NR11 R11 ', -NR13 R13 ', -Alkyl (C0 -C6 ) -Cy1 Or pendant oxygen, ¨ R6 And R7 Independently represent a hydrogen atom, a halogen atom, a straight chain or a branched chain (C1 -C6 ) Alkyl, linear or branched (C2 -C6 ) Alkenyl, linear or branched (C2 -C6 ) Alkynyl, linear or branched (C1 -C6 ) Polyhaloalkyl, hydroxy, linear or branched (C1 -C6 ) Alkoxy, -S- (C1 -C6 ) Alkyl, cyano, nitro, -alkyl (C0 -C6 ) -NR11 R11 ', -O-alkyl (C1 -C6 ) -NR11 R11 ', -O-Cy1 , -Alkyl (C0 -C6 ) -Cy1 , -Alkenyl (C2 -C6 ) -Cy1 , -Alkynyl (C2 -C6 ) -Cy1 , -O-alkyl (C1 -C6 ) -R12 , -C (O) -OR11 , -O-C (O) -R11 , -C (O) -NR11 R11 ', -NR11 -C (O) -R11 ', -NR11 -C (O) -OR11 ', -Alkyl (C1 -C6 ) -NR11 -C (O) -R11 ', -SO2 -NR11 R11 'Or -SO2 -Alkyl (C1 -C6 ), Or (R6 , R7 ) Pairs of substituents, when grafted on two adjacent carbon atoms, together with the carbon atom carrying it, form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it should be understood that the resulting ring may be substituted with a group selected from the group consisting of a straight or branched chain (C1 -C6 ) Alkyl, -NR13 R13 ', -Alkyl (C0 -C6 ) -Cy1 Or pendant oxygen, ¨ W means -CH2 -Group, -NH- group or oxygen atom, ¨ R8 Represents a hydrogen atom, straight or branched chain (C1 -C8 ) Alkyl, -CHRa Rb Group, aryl, heteroaryl, arylalkyl (C1 -C6 ) Group or heteroarylalkyl (C1 -C6 ) Group, ¨ R9 Represents a hydrogen atom, straight or branched chain (C1 -C6 ) Alkyl, linear or branched (C2 -C6 ) Alkenyl, linear or branched (C2 -C6 ) Alkynyl, -Cy2 , -Alkyl (C1 -C6 ) -Cy2 , -Alkenyl (C2 -C6 ) -Cy2 , -Alkynyl (C2 -C6 ) -Cy2 , -Cy2 -Cy3 , -Alkynyl (C2 -C6 ) -O-Cy2 , -Cy2 -Alkyl (C0 -C6 ) -O-alkyl (C0 -C6 ) -Cy3 , Halogen atom, cyano, -C (O) -R14 Or -C (O) -NR14 R14 ', ¨ R10 Represents a hydrogen atom, straight or branched chain (C1 -C6 ) Alkyl, linear or branched (C2 -C6 ) Alkenyl, linear or branched (C2 -C6 ) Alkynyl, arylalkyl (C1 -C6 ) Group, cycloalkylalkyl (C1 -C6 ) Group, linear or branched (C1 -C6 Polyhaloalkyl or -alkyl (C1 -C6 ) -O-Cy4 , Or (R9 , R10 ) Pairs of substituents, when grafted on two adjacent carbon atoms, together with the carbon atom carrying it, form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, ¨ R11 And R11 'Independent of each other means a hydrogen atom, optionally substituted straight or branched chain (C1 -C6 ) Alkyl or -alkyl (C0 -C6 ) -Cy1 , Or (R11 , R11 ') A pair of substituents together with the nitrogen atom carrying it forms an aromatic or non-aromatic ring composed of 5 to 7 ring members, wherein in addition to the nitrogen atom, it may contain 1 to 3 selected from oxygen and sulfur And nitrogen heteroatoms, it should be understood that the nitrogen in question may represent a hydrogen atom or a straight or branched chain by 1 to 2 (C1 -C6 ) Alkyl group substitution, and it should be understood that one or more carbon atoms of possible substituents may be deuterated, ¨ R12 Means -Cy5 , -Cy5 -Alkyl (C0 -C6 ) -O-alkyl (C0 -C6 ) -Cy6 , -Cy5 -Alkyl (C0 -C6 ) -Cy6 , -Cy5 -Alkyl (C0 -C6 ) -NR11 -Alkyl (C0 -C6 ) -Cy6 , -Cy5 -Cy6 -O-alkyl (C0 -C6 ) -Cy7 , -Cy5 -Alkyl (C0 -C6 ) -O-alkyl (C0 -C6 ) -Cy9 , -Cy5 -Alkyl (C0 -C6 ) -Cy9 , -NH-C (O) -NH-R11 , -Cy5 -Alkyl (C0 -C6 ) -NR11 -Alkyl (C0 -C6 ) -Cy9 , -C (O) -NR11 R11 ', -NR11 R11 ', -OR11 , -NR11 -C (O) -R11 ', -O-alkyl (C1 -C6 ) -OR11 , -SO2 -R11 , -C (O) -OR11 ,,orThe ammonium thus defined may exist in the form of zwitterions or have a monovalent counter ion, ¨ R13 , R13 ', R14 And R14 'Independent of each other means a hydrogen atom or optionally substituted straight or branched chain (C1 -C6 ) Alkyl, ¨ Ra Represents a hydrogen atom or a straight or branched chain (C1 -C6 ) Alkyl, ¨ Rb Represents -O-C (O) -O-Rc Group, -O-C (O) -NRc Rc 'Group or -O-P (O) (ORc )2 Group, ¨ Rc And Rc 'Independently of each other means a hydrogen atom, a straight or branched chain (C1 -C8 ) Alkyl, cycloalkyl, (C1 -C6 ) Alkoxy (C1 -C6 ) Alkyl, or (C1 -C6 ) Alkoxycarbonyl (C1 -C6 ) Alkyl, or (Rc , Rc ') The pair of substituents together with the nitrogen atom carrying it forms a non-aromatic ring consisting of 5 to 7 ring members, wherein in addition to the nitrogen atom, it may further contain 1 to 3 heteroatoms selected from oxygen and nitrogen It should be understood that the nitrogen in question may be represented by a straight or branched chain (C1 -C6 ) Alkyl group substitution, ¨ Cy1 , Cy2 , Cy3 , Cy4 , Cy5 , Cy6 , Cy7 , Cy8 And Cy10 Independently of each other represent cycloalkyl, heterocycloalkyl, aryl or heteroaryl, ¨ Cy9 Express, Or Cy9 Represents a heteroaryl group substituted with a group selected from: -O-P (O) (OR20 )2 ; -O-P (O) (O- M+ )2 ;-( CH2 )p -O- (CHR18 -CHR19 -O)q -R20 ; Hydroxyl; hydroxyl (C1 -C6 ) Alkyl;-(CH2 )r -U- (CH2 )s -Heterocycloalkyl; or -U- (CH2 )q -NRtwenty one Rtwenty one ', ¨ R15 Represents a hydrogen atom;-(CH2 )p -O- (CHR18 -CHR19 -O)q -R20 Group; straight or branched (C1 -C6 ) Alkoxy (C1 -C6 ) Alkyl; -U- (CH2 )q -NRtwenty one Rtwenty one 'Group; or-(CH2 )r -U- (CH2 )s -Heterocycloalkyl, ¨ R16 Represents a hydrogen atom; hydroxyl; hydroxyl (C1 -C6 ) Alkyl;-(CH2 )r -U- (CH2 )s -Heterocycloalkyl; (CH2 )r -U-V-O-P (O) (OR20 )2 Group; -O-P (O) (O- M+ )2 Group;-(CH2 )p -O- (CHR18 -CHR19 -O)q -R20 Group;-(CH2 )p -O-C (O) -NRtwenty two Rtwenty three Group; or -U- (CH2 )q -NRtwenty one Rtwenty one 'Group, ¨ R17 Represents a hydrogen atom;-(CH2 )p -O- (CHR18 -CHR19 -O)q -R20 Group; -O-P (O) (OR20 )2 Group; -O-P (O) (O- M+ )2 Group; hydroxyl;1 -C6 ) Alkyl;-(CH2 )r -U- (CH2 )s -Heterocycloalkyl; -U- (CH2 )q -NRtwenty one Rtwenty one 'Group; or aldonic acid, ¨ M+ Represents a pharmaceutically acceptable monovalent cation, ¨ U represents a bond or an oxygen atom, ¨ V represents-(CH2 )s -Group or -C (O)-group, ¨ R18 Represents a hydrogen atom or (C1 -C6 ) Alkoxy (C1 -C6 ) Alkyl, ¨ R19 Represents a hydrogen atom or a hydroxyl group (C1 -C6 ) Alkyl, ¨ R20 Represents a hydrogen atom or a straight or branched chain (C1 -C6 ) Alkyl, ¨ Rtwenty one And Rtwenty one 'Independently of each other means a hydrogen atom, a straight or branched chain (C1 -C6 ) Alkyl or hydroxy (C1 -C6 ) Alkyl, or (Rtwenty one , Rtwenty one ') A pair of substituents together with the nitrogen atom carrying it forms an aromatic or non-aromatic ring composed of 5 to 7 ring members, wherein in addition to the nitrogen atom, it may contain 1 to 3 selected from oxygen and sulfur And nitrogen heteroatoms, it should be understood that the resulting ring may represent a hydrogen atom or a straight or branched chain (C1 -C6 ) Alkyl group substitution, ¨ Rtwenty two Means (C1 -C6 ) Alkoxy (C1 -C6 ) Alkyl,-(CH2 )p -NRtwenty four Rtwenty four 'Group or-(CH2 )p -O- (CHR18 -CHR19 -O)q -R20 Group, ¨ Rtwenty three Represents a hydrogen atom or (C1 -C6 ) Alkoxy (C1 -C6 ) Alkyl, or (Rtwenty two , Rtwenty three ) A pair of substituents together with the nitrogen atom carrying it forms an aromatic or non-aromatic ring consisting of 5 to 18 ring members, which may contain 1 to 5 members selected from oxygen, sulfur, and nitrogen in addition to the nitrogen atom. Heteroatom, it should be understood that the resulting ring may be represented by a hydrogen atom, a straight chain or a branched chain (C1 -C6 ) Alkyl or heterocycloalkyl group substitution, ¨ Rtwenty four And Rtwenty four 'Independently of each other means a hydrogen atom or a straight or branched chain (C1 -C6 ) Alkyl, or (Rtwenty four , Rtwenty four ') A pair of substituents together with the nitrogen atom carrying it forms an aromatic or non-aromatic ring composed of 5 to 7 ring members, wherein in addition to the nitrogen atom, it may further contain 1 to 3 selected from oxygen and sulfur And nitrogen heteroatoms, it should be understood that the resulting ring may be represented by a hydrogen atom or a straight or branched chain (C1 -C6 ) Alkyl group substitution, ¨ R25 Represents a hydrogen atom, a hydroxyl group, or a hydroxyl group (C1 -C6 ) Alkyl, ¨ R26 Represents a hydrogen atom, a halogen atom, a straight or branched chain (C1 -C6 ) Alkyl or cyano, ¨ R27 Represents a hydrogen atom or a straight or branched chain (C1 -C6 ) Alkyl, ¨ R28 Represents -O-P (O) (O- ) (O- ) Group, -O-P (O) (O- ) (OR30 ) Group, -O-P (O) (OR30 ) (OR30 ') Group, -O-SO2 -O- Group, -O-SO2 -OR30 Group, -Cy10 , -O-C (O) -R29 Group, -O-C (O) -OR29 Group or -O-C (O) -NR29 R29 'Group; ¨ R29 And R29 'Independently of each other means a hydrogen atom, a straight or branched chain (C1 -C6 ) Alkyl or linear or branched amine (C1 -C6 ) Alkyl, ¨ R30 And R30 'Independently of each other means a hydrogen atom, a straight or branched chain (C1 -C6 ) Alkyl or arylalkyl (C1 -C6 ) Group, ¨ n is an integer equal to 0 or 1, ¨ p is an integer equal to 0, 1, or 2, ¨ q is an integer equal to 1, 2, 3, or 4, and r and s are independently equal to 0 or An integer of one, it should be understood:-"aryl" means phenyl, naphthyl, biphenyl, indanyl or indenyl,-"heteroaryl" means any single group consisting of 5 to 10 ring members A cyclic or bicyclic group having at least one aromatic moiety and containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen,-"cycloalkyl" means any monocyclic or Bicyclic non-aromatic carbocyclyl,-"heterocycloalkyl" means any monocyclic or bicyclic non-aromatic carbon containing 3 to 10 ring members and 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen A cyclic group, which may include a fused ring, a bridged ring, or a spiro ring system. The aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups and alkyl, alkenyl, alkynyl, and alkoxy groups as defined may Substitution of up to 4 groups: optionally substituted straight or branched chain (C1 -C6 ) Alkyl, optionally substituted straight or branched chain (C2 -C6 ) Alkenyl, optionally substituted straight or branched chain (C2 -C6 ) Alkynyl, optionally substituted straight or branched chain (C1 -C6 ) Alkoxy, optionally substituted (C1 -C6 ) Alkyl-S-, hydroxyl, pendant (or, where appropriate,N -Oxide), nitro, cyano, -C (O) -OR ', -OC (O) -R', -C (O) -NR'R '', -NR'R '',-( C = NR ')-OR' ', straight or branched chain (C1 -C6 ) Polyhaloalkyl, trifluoromethoxy or halogen, it should be understood that R ′ and R ″ independently of each other represent a hydrogen atom or optionally substituted straight or branched chain (C1 -C6 ) Alkyl, and it should be understood that one or more of the carbon atoms of the foregoing possible substituents may be deuterated, or an enantiomer, diastereomer, or atropisomer thereof, or a pharmaceutical Additive salts of academically acceptable acids or bases, and (b) taxane compounds for simultaneous, sequential, or separate use. A further enumerated example (E) of the invention is described herein. It should be recognized that features specified in various embodiments may be combined with other specified features to provide other embodiments of the present invention. E2. The combination according to E1, comprising: (a) an MCL-1 inhibitor of formula (II), ie a special case of an MCL-1 inhibitor of formula (I):Where: ¨ Z represents a nitrogen atom or C-R4 Group, ¨ R1 Represents a straight or branched chain (C1 -C6 ) Alkyl, linear or branched (C2 -C6 ) Alkenyl, linear or branched (C2 -C6 ) Alkynyl, linear or branched (C1 -C6 ) Alkoxy, -S- (C1 -C6 ) Alkyl, linear or branched (C1 -C6 ) Polyhaloalkyl, hydroxyl, cyano, -NR11 R11 ', -Cy8 Or a halogen atom, ¨ R2 , R3 And R4 Independently represent a hydrogen atom, a halogen atom, a straight chain or a branched chain (C1 -C6 ) Alkyl, linear or branched (C2 -C6 ) Alkenyl, linear or branched (C2 -C6 ) Alkynyl, linear or branched (C1 -C6 ) Polyhaloalkyl, hydroxy, linear or branched (C1 -C6 ) Alkoxy, -S- (C1 -C6 ) Alkyl, cyano, nitro, -alkyl (C0 -C6 ) -NR11 R11 ', -O-Cy1 , -Alkyl (C0 -C6 ) -Cy1 , -Alkenyl (C2 -C6 ) -Cy1 , -Alkynyl (C2 -C6 ) -Cy1 , -O-alkyl (C1 -C6 ) -R12 , -C (O) -OR11 , -O-C (O) -R11 , -C (O) -NR11 R11 ', -NR11 -C (O) -R11 ', -NR11 -C (O) -OR11 ', -Alkyl (C1 -C6 ) -NR11 -C (O) -R11 ', -SO2 -NR11 R11 'Or -SO2 -Alkyl (C1 -C6 ), Or (R2 , R3 ), (R3 , R4 ) Wherein a pair of substituents together with the carbon atom carrying it forms an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, It should be understood that the resulting ring may be substituted with a group selected from the group consisting of a straight or branched chain (C1 -C6 ) Alkyl group, -NR13 R13 ', -Alkyl (C0 -C6 ) -Cy1 Or pendant oxygen, ¨ R6 And R7 Independently represent a hydrogen atom, a halogen atom, a straight chain or a branched chain (C1 -C6 ) Alkyl, linear or branched (C2 -C6 ) Alkenyl, linear or branched (C2 -C6 ) Alkynyl, linear or branched (C1 -C6 ) Polyhaloalkyl, hydroxy, linear or branched (C1 -C6 ) Alkoxy, -S- (C1 -C6 ) Alkyl, cyano, nitro, -alkyl (C0 -C6 ) -NR11 R11 ', -O-Cy1 , -Alkyl (C0 -C6 ) -Cy1 , -Alkenyl (C2 -C6 ) -Cy1 , -Alkynyl (C2 -C6 ) -Cy1 , -O-alkyl (C1 -C6 ) -R12 , -C (O) -OR11 , -O-C (O) -R11 , -C (O) -NR11 R11 ', -NR11 -C (O) -R11 ', -NR11 -C (O) -OR11 ', -Alkyl (C1 -C6 ) -NR11 -C (O) -R11 ', -SO2 -NR11 R11 'Or -SO2 -Alkyl (C1 -C6 ), Or (R6 , R7 ) Pairs of substituents, when grafted on two adjacent carbon atoms, together with the carbon atom carrying it, form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it should be understood that the resulting ring may be substituted with a group selected from the group consisting of a straight or branched chain (C1 -C6 ) Alkyl, -NR13 R13 ', -Alkyl (C0 -C6 ) -Cy1 Or pendant oxygen, ¨ R8 Represents a hydrogen atom, straight or branched chain (C1 -C8 ) Alkyl, aryl, heteroaryl, arylalkyl (C1 -C6 ) Group or heteroarylalkyl (C1 -C6 ) Group, ¨ R9 Represents a hydrogen atom, straight or branched chain (C1 -C6 ) Alkyl, linear or branched (C2 -C6 ) Alkenyl, linear or branched (C2 -C6 ) Alkynyl, -Cy2 , -Alkyl (C1 -C6 ) -Cy2 , -Alkenyl (C2 -C6 ) -Cy2 , -Alkynyl (C2 -C6 ) -Cy2 , -Cy2 -Cy3 , -Alkynyl (C2 -C6 ) -O-Cy2 , -Cy2 -Alkyl (C0 -C6 ) -O-alkyl (C0 -C6 ) -Cy3 , Halogen atom, cyano, -C (O) -R14 Or -C (O) -NR14 R14 ', ¨ R11 And R11 'Independent of each other means a hydrogen atom, optionally substituted straight or branched chain (C1 -C6 ) Alkyl or -alkyl (C0 -C6 ) -Cy1 , Or (R11 , R11 ') A pair of substituents together with the nitrogen atom carrying it forms an aromatic or non-aromatic ring composed of 5 to 7 ring members, wherein in addition to the nitrogen atom, it may further contain 1 to 3 selected from oxygen and sulfur And nitrogen heteroatoms, it should be understood that the nitrogen in question may represent a hydrogen atom or a straight or branched chain (C1 -C6 ) Alkyl group substitution, and it should be understood that one or more carbon atoms of possible substituents may be deuterated, ¨ R12 Means -Cy5 , -Cy5 -Alkyl (C0 -C6 ) -O-alkyl (C0 -C6 ) -Cy6 , -Cy5 -Alkyl (C0 -C6 ) -O-alkyl (C0 -C6 ) -Cy6 , -Cy5 -Alkyl (C0 -C6 ) -NR11 -Alkyl (C0 -C6 ) -Cy6 , -Cy5 -Cy6 -O-alkyl (C0 -C6 ) -Cy7 , -C (O) -NR11 R11 ', -NR11 R11 ', -OR11 , -NR11 -C (O) -R11 ', -O-alkyl (C1 -C6 ) -OR11 , -SO2 -R11 , -C (O) -OR11 Or -NH-C (O) -NH-R11 , ¨ R13 , R13 ', R14 And R14 'Independent of each other means a hydrogen atom or optionally substituted straight or branched chain (C1 -C6 ) Alkyl, ¨ R25 Represents a hydrogen atom, a hydroxyl group, or a hydroxyl group (C1 -C6 ) Alkyl, ¨ Cy1 , Cy2 , Cy3 , Cy5 , Cy6 , Cy7 And Cy8 Each independently represents a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, and n is an integer equal to 0 or 1, it should be understood that: "aryl" means phenyl, naphthyl, biphenyl, Indanyl or indenyl,-"heteroaryl" means any monocyclic or bicyclic group consisting of 5 to 10 ring members, which has at least one aromatic moiety and contains 1 to 3 selected from oxygen, sulfur And nitrogen heteroatoms,-"cycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members,-"heterocycloalkyl" means any group containing 3 to 10 rings A monocyclic or bicyclic non-aromatic carbocyclic member of a member and containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which may include fused ring, bridged ring or spiro ring systems, such as aryl, heteroaryl Groups, cycloalkyl and heterocycloalkyl groups, and alkyl, alkenyl, alkynyl, and alkoxy groups may be substituted with 1 to 4 groups selected from the following: optionally substituted straight or branched chain (C1 -C6 ) Alkyl, optionally substituted straight or branched chain (C2 -C6 ) Alkenyl, optionally substituted straight or branched chain (C2 -C6 ) Alkynyl, optionally substituted straight or branched chain (C1 -C6 ) Alkoxy, optionally substituted (C1 -C6 ) Alkyl-S-, hydroxyl, pendant (or, where appropriate,N -Oxide), nitro, cyano, -C (O) -OR ', -OC (O) -R', -C (O) -NR'R '', -NR'R '',-( C = NR ')-OR' ', straight or branched chain (C1 -C6 ) Polyhaloalkyl, trifluoromethoxy or halogen, it should be understood that R ′ and R ″ independently of each other represent a hydrogen atom or optionally substituted straight or branched chain (C1 -C6 ) Alkyl, and it should be understood that one or more of the carbon atoms of the foregoing possible substituents may be deuterated, or an enantiomer, diastereomer, or atropisomer thereof, or a pharmaceutical Additive salts of academically acceptable acids or bases, and (b) taxane compounds for simultaneous, sequential, or separate use. E3. The combination according to E1 or E2, wherein the taxane compound is paclitaxel or docetaxel. E4. The combination according to E1 or E2, wherein the MCL-1 inhibitor is (2R ) -2-{[(5S a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl ) Thieno [2,3-d ] Pyrimidin-4-yl] oxy} -3- (2-{[1- (2,2,2-trifluoroethyl) -1H -Pyrazol-5-yl] methoxy} phenyl) propionic acid. E5. The combination according to E1 or E2, wherein the MCL-1 inhibitor is (2R ) -2-{[(5S a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d ] Pyrimidin-4-yl] oxy} -3- (2-{[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propionic acid. E6. The combination according to E1 or E2, wherein the taxane compound is paclitaxel. E7. The combination according to E1 or E2, wherein the taxane compound is docetaxel. E8. The combination according to E1 or E2, wherein the MCL-1 inhibitor is (2R ) -2-{[(5S a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d ] Pyrimidin-4-yl] oxy} -3- (2-{[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propionic acid and the taxane compound is Paclitaxel. E9. The combination according to E1 or E2, wherein the MCL-1 inhibitor is (2R ) -2-{[(5S a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl ) Thieno [2,3-d ] Pyrimidin-4-yl] oxy} -3- (2-{[1- (2,2,2-trifluoroethyl) -1H -Pyrazol-5-yl] methoxy} phenyl) propionic acid and the taxane compound is paclitaxel. E10. The combination according to E1 or E2, wherein the MCL-1 inhibitor is (2R ) -2-{[(5S a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d ] Pyrimidin-4-yl] oxy} -3- (2-{[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propionic acid and the taxane compound is Docetaxel. E11. The combination according to E1 or E2, wherein the MCL-1 inhibitor is (2R ) -2-{[(5S a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl ) Thieno [2,3-d ] Pyrimidin-4-yl] oxy} -3- (2-{[1- (2,2,2-trifluoroethyl) -1H -Pyrazol-5-yl] methoxy} phenyl) propionic acid and the taxane compound is docetaxel. E12. The combination according to E5, wherein during the combination therapy (2R ) -2-{[(5S a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d ] Pyrimidin-4-yl] oxy} -3- (2-{[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propionic acid in a dose of 25 mg to 1500 mg. E13. The combination according to E5 or E12, wherein (2R ) -2-{[(5S a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d ] Pyrimidin-4-yl] oxy} -3- (2-{[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propanoic acid once a week. E14. The combination according to any one of E1 to E13, wherein the MCL-1 inhibitor is administered orally and the taxane compound is administered intravenously. E15. The combination according to any one of E1 to E13, wherein the MCL-1 inhibitor and the taxane compound are administered intravenously. E16. The combination according to any one of E1 to E15, for use in treating cancer. E17. The combination according to E16, wherein the MCL-1 inhibitor and the taxane compound are provided in an amount effective for co-therapeutic treatment of cancer. E18. The combination according to E16, wherein the MCL-1 inhibitor and the taxane compound are provided in an amount synergistically effective for cancer treatment. E19. The combination according to E16, wherein the MCL-1 inhibitor and the taxane compound are provided in a synergistically effective amount capable of reducing the required dose of each compound in cancer treatment, while providing effective cancer treatment, and ultimately reducing side effects. E20. The combination according to any one of E16 to E19, wherein the cancer is breast cancer. E21. The combination according to E20, wherein the cancer is triple negative breast cancer, especially chemoresistant triple negative breast cancer, more specifically, triple negative breast cancer resistant to taxane therapy. E22. The combination according to any one of E16 to E19, wherein the cancer is lung cancer, especially non-small cell lung cancer or small cell lung cancer. E23. The combination according to any one of E1 to E15, further comprising one or more excipients. E24. A pharmaceutical composition comprising a combination according to any one of E1 to E15, in combination with one or more pharmaceutically acceptable excipients. E25. The pharmaceutical composition according to E24, for use in treating cancer. E26. The pharmaceutical composition according to E25, wherein the cancer is breast cancer. E27. The pharmaceutical composition according to E26, wherein the cancer is a triple negative breast cancer, especially a chemically resistant triple negative breast cancer, and more specifically, a triple negative breast cancer resistant to taxane therapy. E28. The pharmaceutical composition combination according to E25, wherein the cancer is lung cancer, especially non-small cell lung cancer or small cell lung cancer. E29. Use of a combination according to any one of E1 to E15 in the manufacture of a medicament for treating cancer. E30. The use according to E29, wherein the cancer is breast cancer. E31. The use according to E30, wherein the cancer is a triple negative breast cancer, especially a chemically resistant triple negative breast cancer, and more specifically, a triple negative breast cancer resistant to taxane therapy. E32. Use according to E29, wherein the cancer is lung cancer, especially non-small cell lung cancer or small cell lung cancer. E33. A medicament comprising, separately or together, (a) an MCL-1 inhibitor of formula (I) as defined in E1, and (b) a taxane compound for simultaneous, sequential or separate administration And wherein the MCL-1 inhibitor and the taxane compound are provided in an effective amount for treating cancer. E34. A drug comprising separately or together, (a) an MCL-1 inhibitor of formula (II) as defined in E2, and (b) a taxane compound for simultaneous, sequential or separate administration And wherein the MCL-1 inhibitor and the taxane compound are provided in an effective amount for treating cancer. E35. A method for treating cancer, comprising administering to a subject in need thereof a co-therapeutic effective amount of each of: (a) an MCL-1 inhibitor of formula (I) as defined in E1, and ( b) Taxane compounds. E36. A method of treating cancer, comprising administering to a subject in need thereof a co-therapeutic effective amount of each of: (a) an MCL-1 inhibitor of formula (II) as defined in E2, and ( b) Taxane compounds. E37. A method for sensitizing a patient who is (i) difficult to treat with at least one chemotherapy or (ii) relapses after treatment with chemotherapy, or (i) and (ii), wherein the method comprises administering to the patient And a therapeutically effective amount of an MCL-1 inhibitor of formula (I) as defined in El and a taxane compound as described herein. E38. A method for sensitizing a patient who is (i) difficult to treat with at least one chemotherapy or (ii) relapses after treatment with chemotherapy, or (i) and (ii), wherein the method comprises administering to the patient A co-therapeutic effective amount of an MCL-1 inhibitor of formula (II) as defined in E2 with a taxane compound as described herein. "Combination" means a fixed-dose combination, a non-fixed-dose combination, or a set of components for combined administration in a unit dosage form (e.g., capsule, lozenge, or sachet), in which the compound of the invention and Or multiple combinations (e.g., another drug as explained below, also known as a "therapeutic agent" or "combined preparation") are administered independently at the same time, or separately at intervals, especially during these times The spacing allows the combination partner to exhibit a cooperative (eg, synergistic) effect. As used herein, the terms "co-administration" or "combination administration" or similar terms are intended to cover the administration of a selected combination partner to a single individual in need (e.g., a patient), and are intended to include where the formulation is not necessarily borrowed The treatment plan is administered by the same administration route or simultaneously. The term "fixed dose combination" means the simultaneous administration of both the active ingredient (such as a compound of formula (I)) and one or more combination partners into one entity or dosage form. The term "non-fixed-dose combination" means that the active ingredient (e.g., a compound of the invention) and one or more combinations are presented as separate entities or dosages, administered simultaneously or sequentially to a patient without specific time restrictions, such as The dosing method provides a therapeutically effective amount of two compounds in a patient. The latter is also suitable for combination therapies, such as the administration of three or more active ingredients. "Cancer" means a disease in which a group of cells exhibits uncontrolled growth. Cancer types include solid tumors, including carcinomas, sarcomas, or blastomas. In particular, "cancer" means breast cancer and lung cancer. The term "co-therapeutic effect" means that the therapeutic agent can be administered separately to warm-blooded animals, especially humans, to be treated at intervals of its preference (in a staggered manner, especially in a specific order), while still showing (preferably Synergistic) interactions (common therapeutic effects). This condition can be determined in particular by tracking blood content, showing that both compounds are simultaneously present in the blood of the human being to be treated at least during certain time intervals. "Synergistically effective" or "synergistic" means that the therapeutic effect observed after the administration of two or more agents is greater than the total therapeutic effect observed after the administration of each single agent. As used herein, the term "treat, treating, or treatment" of any disease or disorder refers in one embodiment to ameliorating the disease or disorder (ie, slowing or suppressing or reducing at least one of the disease or its clinical symptoms). Development). In another embodiment, "treat, treating, or treatment" refers to alleviating or improving at least one physical parameter, including physical parameters that the patient may not be able to discern. In yet another embodiment, "treat, treating, or treating "Treatment" means regulating a disease or condition physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing a body parameter), or physically and physiologically. As used herein, if an individual will biologically , Medically or quality of life benefit from treatment, the individual "needs" the treatment. In another aspect, a method is provided for making (i) difficult to treat with at least one chemotherapy or (ii) treatment with chemotherapy A patient-sensitive method that subsequently relapses or (i) and (ii), wherein the method comprises administering to the patient an MCL-1 inhibitor of formula (I) or formula (II) and a taxus as described herein Compounds. Sensitized patients have responded to or have not developed treatments involving the administration of an MCL-1 inhibitor of formula (I) or formula (II) with a taxane compound as described herein Resistant patients. "Drug" means the medical group Or a combination of several pharmaceutical compositions containing one or more active ingredients in the presence of one or more excipients. In the pharmaceutical composition according to the present invention, the weight ratio of active ingredients (combination of weight ratios of active ingredients The total weight of the substances) is from 5% to 50%. In the pharmaceutical composition according to the invention, more particularly, oral, parenteral and especially intravenous, whole skin or anti-skin, nasal, rectal, Those administered by the tongue, eyes or respiratory tract, more precisely, lozenges, dragees, sublingual lozenges, hard gelatin capsules, rectal dosage forms, capsules, oral tablets, injectable preparations, sprays, Eye or nasal drops, suppositories, creams, ointments, transdermal gels, etc. The pharmaceutical composition according to the present invention comprises one or more pharmaceutically acceptable excipients or carriers selected from diluents, lubricants Agents, binders, disintegrating agents, stabilizers, preservatives, adsorbents, colorants, sweeteners, flavoring agents, etc.By way of non-limiting example, mention may be made of: w as a diluent: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol, w as a lubricant: silicon dioxide, talc, stearic acid and its magnesium and calcium salts, polyethylene Diol, w as a binder: magnesium aluminum silicate, starch, gelatin, baicale, methyl cellulose, sodium carboxymethyl cellulose and polyvinylpyrrolidone, w as a disintegrant: agar, alginic acid and its Sodium salt, foaming mixture. The combined compounds can be administered simultaneously or sequentially. The route of administration is preferably intravenous infusion or injection, and the corresponding pharmaceutical composition can achieve instant or delayed release of the active ingredient. The combined compounds may also be administered in the form of two separate pharmaceutical compositions each containing one of the active ingredients, or in the form of a single pharmaceutical composition in which the active ingredients are in the form of a mixture. Available dosing regimens vary according to the sex, age, and weight of the patient; the route of administration; the nature of the cancer and any related treatment, and range from 25 mg to 1500 mg per week, more preferably from 50 mg to 1400 mg per week. MCL-1 Inhibitor range. The dosage of the taxane compound will be the same as when it is administered alone.Pharmacological information Examples 1: Combination in breast and lung cancer cell lines MCL - 1 Inhibitor ( Compound 1 ) versus In vitro effects of paclitaxel on proliferation In 19 breast cancer cell lines (BT-20, BT-474, BT-549, Cal-148, HCC1143, HCC1395, HCC1500, HCC1937, HCC1954, HCC38, HCC70, Hs 578T, MCF7, MDA-MB-157, MDA- MB-231, MDA-MB-436, MDA-MB-453, MDA-MB-468, and SK-BR-3) and three lung cancer cell lines (H522, H23, and A549) were evaluated in combination with MCL-1 inhibition Effect of Compound (Compound 1) and Paclitaxel on Proliferation. Materials and methods The compound was dissolved in 100% DMSO (Sigma, catalog # D2438-50ML) at a raw material concentration of 10 mM and stored at -20 ° C until use. Compounds were arranged in 2 ml deep 96-well plates (Greiner bio-one, catalog number 780271) and serially diluted 3-fold. Compound 1 is used at a concentration in the range of 0.0 to 10.0 μM. Paclitaxel is used at a concentration ranging from 0.0 to 1.0 μM in breast cancer cells and at a concentration ranging from 0.0 to 2.0 μM in lung cancer cells. All cell lines were purchased from the American Type Culture Collection and cultured according to supplier recommendations. All cell lines were supplemented with 10% FBS (GIBCO, catalog number 10099-141). All cell lines were determined to be free of mold contamination by PCR detection analysis using Idexx Radil (Columbia, MO, USA) and verified by SNP analysis. Thaw cells from frozen material, expand via ≥1 passage and 5% CO at 37 ° C2 Medium growth. Cells were expanded into T-75 flasks and assessed for viability using a Beckman-Coulter ViCell counter before seeding. To isolate and expand the cell line, cells were removed from the flask using 0.25% trypsin-EDTA (Corning Costar, catalog # 25-053-CL). With 72 hours CellTiter-GloTM (CTG) analysis to measure cell proliferation and all results presented are the results of at least triplicate measurements. Cells were dispensed into tissue culture-treated 96-well dishes (Costar, Cat. No. 3904) at a final volume of 80 μL medium and a density of 3000 cells per well. After 16 to 24 hours of inoculation, 20 μL of each compound dilution series was transferred to a cell-containing plate, resulting in the above-mentioned compound concentration range and a final DMSO concentration of 0.16%. In addition, as described below, the CellTiter-Glo® Luminescent Cell Viability Analysis was used to analyze day zero discs. CellTiter-Glo ™ Luminescent Cell Viability Assay (Promega, Cat # G7573) was used to determine the effect of compounds on cell proliferation after 72 hours of compound treatment. This is a homogeneous method of determining the number of living cells in culture based on quantifying the presence of ATP, which indicates the presence of metabolically active cells. The method is described in detail in Technical Bulletin, TB288 Promega. Briefly, 100 μl of CTG reagent was added to the plate, and the plate was incubated on an orbital shaker for 20 to 30 minutes. Will be listed on Perkin Elmer VictorTM Read on X4 disk reader. The Combo Module software was used to calculate the percentage growth inhibition, excess inhibition, and growth inhibition using the Lowy synergy model (as in Lehar et al.,Nature Biotechnology 2009, 27 (7), 659-66), this Lowy synergy model measures the degree to which growth should be expected to be expected if two drugs appear in a dose-additive fashion. Positive numbers indicate areas where synergy is increased. The percentage of growth inhibition relative to DMSO is marked as "inhibition "Is shown in the figure. The amount of inhibition that exceeds the expected amount is marked as"Lowy excessive suppression ". The amount of inhibition normalized to day zero is marked as"Growth inhibition "Is shown in the figure. The concentration of compound 1 is shown from left to right along the bottom column and the increased concentration of paclitaxel is shown from bottom to top along the leftmost column. All the remaining points in the grid are shown corresponding to the representation on two axes The result of the combination of two inhibitors at a single agent concentration. The absolute IC was determined by finding the concentration of the compound whose calculated curve exceeded 50% of the active label.50 . Calculate Absolute IC in Combo Module Software50 And synergy scores, as described in Lehar et al. 2009.Collaborative score SS ~ 0 → Dose addition SS ＞ 2 → Synergy SS ＞ 1 → Weak synergytable 1. Indicate a single agent absolute IC for each compound50 Value and the synergy score of the combination of compound 1 and paclitaxel. When a score of ≥2.0 is observed, the interaction is considered synergistic. result Compound 1 as a single agent inhibits the growth of 7/19 breast cancer cell lines and 2/3 lung cancer cell lines, IC50 Below 1000 nM (Table 1). Paclitaxel as a single agent inhibits the growth of 17/19 breast cancer cell lines and 3/3 lung cancer cell lines, IC50 Below 1000 nM. In combination, Compound 1 and paclitaxel treatment caused synergistic growth inhibition (i.e., a synergy score higher than 2 (Lehar et al., 2009)) in 16/19 breast cancer cell lines and 3/3 lung cancer cell lines (Table 1). The synergy was obvious in 11 cell lines, and the synergy score was higher than 6. Importantly, synergy does not depend on the antiproliferative effect of a single agent, and synergy occurs across a wide range of single agent concentrations (Figures 1, 2 and 3), which should demonstrate flexibility in terms of dosing levels and protocols Beneficial in vivo.Examples 2 : Combination in breast and lung cancer cell lines MCL - 1 Inhibitor ( Compound 2 ) And in vitro effects of paclitaxel on proliferation The effects of the combination of MCL-1 inhibitor (compound 2) and paclitaxel on proliferation were evaluated in a map of two breast cancer cell lines (MDA-MB-453 and MDA-MB-468) and one lung cancer cell line (H522). Materials and methods Cell lines were obtained and maintained in basal medium supplemented with fetal bovine serum as indicated in Table 2. In addition, all media contained penicillin (100 IU / ml), streptomycin (100 µg / ml), and L-glutamic acid (2 mM). Place the cell line at 37 ° C under 5% CO2 Incubate in a humid atmosphere and expand in a T-150 flask. In all cases cells were thawed from frozen stock, expanded via ≥1 generation using appropriate dilutions, counted and assessed for viability using a CASY cytometer, and then seeded at a density as indicated in Table 2 to a 96-well plate in. All cell lines were determined to be free of mold contamination inside. A stock solution of the compound was prepared at a concentration of 5 mM in DMSO and stored at -20 ° C. To analyze the activity of the compounds in a single agent or in a combination, seed the cells and directly with seven or eight 3.16-fold serial dilutions of each assigned compound individually or in all possible arrangements in a checkerboard format Process into a cell analysis plate as indicated in Figures 5 and 6. After 3 days of incubation, the effects of a single agent and its checkerboard combination on cell viability were evaluated. The analysis was performed at 37 ° C / 5% CO2 The following was performed using CellTiterGlo to quantify cell ATP levels at 75 μL reagent / well. At least two independent experiments were performed, each performed in duplicate. Quantitative luminescence on a multi-purpose disk reader. Calculate single-drug IC using standard four-parameter curve fit50 . Potential synergistic interactions between compound combinations were evaluated using a Loy addition model using an excess inhibition 2D matrix and reported as a synergy score (Lehar et al. 2009). All calculations use Chalice available on the Horizon websiteTM Bioinformatics software. The doubling times indicated in Table 2 are the average of the doubling times obtained from the thawing of the cells to the different passages (in a T-150 flask) that they inoculated in the 96-well plate.Collaborative score SS ~ 0 → Add SS ＞ 1 → If weak cooperation SS ＞ 2 → Cooperationtable 2. Identification and analysis conditions of cell lines used in combination experiments. table 3. Single-agent IC for indicator compound 2 and paclitaxel50 value. The compound was incubated with the cells over a period of 3 days. table 4. Synergy score for combination of compound 2 and paclitaxel. When the observed score is ≥2.0, the interaction is considered synergistic. Indicates the starting concentration of the compound, the mean of the maximum inhibition, and the standard deviation (sd) of the synergy score. The compound was incubated with the cells over a period of 3 days. result Compound 2 as a single agent inhibited the growth of 1/3 of the cell lines tested, and the IC of H522 cell line50 140 nM (Table 3). Paclitaxel as a single agent inhibits the growth of 2/3 of the cell lines tested, and IC50 Below 1 nM. Of the three cell lines tested, Compound 2 and paclitaxel treatment in combination caused synergistic growth inhibition (ie, a synergy score higher than 2 (Lehar et al. 2009)) (Table 4). The synergy was obvious in the two cell lines, with a synergy score of 6.5 and 16.9. Importantly, synergy does not depend on the anti-proliferative effect of a single agent, and synergistic effects occur across a wide range of single agent concentrations (Figures 4 and 5), which should prove beneficial in vivo in terms of flexibility of dosing levels and flexibility .Examples 3 : In vitro MCL - 1 Synergy between inhibitors and docetaxel We investigated whether MCL-1 inhibitor (compound 2) elicited synergistic activity with agents currently used in TNBC treatment. Compound 2 was combined with docetaxel in SK-BR-3 cells. Materials and methods Cell line : The breast cancer cell line SK-BR-3 was maintained in RPMI-1640 plus GlutaMAX-1 (Gibco) supplemented with 10% fetal calf serum (FCS) and 10 µg / ml insulin. For viability analysis, place cells at 2 × 10 in a 96-well plate5 Cells / ml were seeded in RPMI-1640 medium (Gibco) supplemented with 10% FCS and 10 μg / ml insulin, and treated with compound 2 at an increased concentration. Cell viability : Cell viability was evaluated using Cell Titer Glo Luminescent Assay (Promega) according to the manufacturer's instructions. A broad-spectrum apoptotic protease inhibitor QVD-OPh hydrate (Sigma-Aldrich) was used at 10 μM. Propidium iodide rejection (5 μg / ml) was analyzed by flow cytometry. For in vitro cell analysis to resolve synergies between different drugs, the Bliss independent method was used (Prichard et al.,Antimicrobial Agents and Chemotherapy 1991, 35, 1060-5) to determine the combined effect. result Docetaxel and MCL-1 inhibitors show significant synergy at extremely low concentrations of the two components. In particular, docetaxel and compound 2 showed significant synergy at extremely low concentrations of docetaxel (2 nM) and compound 2 (31 nM) (Figures 6 and 7). Inhibition of apoptotic protease and pan-caspase inhibitor QVD-OPH effectively blocked cell death, confirming that the cell death line was triggered by apoptosis (Figure 6).Examples 4 : In vivo MCL - 1 Inhibit PDX Tumors are sensitive to taxane treatment Because in vitro analysis revealed that breast cancer cell lines are sensitive to Compound 2 in combination therapy, we next determined its in vivo therapeutic effect in three PDX models representing three TNBCs (110T, 838T, and PDX OD-BRE-0589). Materials and methods Human breast cancer tissues were obtained from consenting patients through the Royal Melbourne Hospital Tissue Bank, Victorian Cancer Biobank, and Georges-Francois Leclerc Center with the approval of relevant institutional review boards. Human ethics approval was obtained from the Walter and Eliza Hall Institute (WEHI) Human Research Ethics Committee and the Georges-Francois Leclerc Center Human Research Ethics Committee. Breed and maintain NOD SCID IL2 gamma receptor knockout mice or SCID mice according to institutional guidelines. All animal experiments were approved by WEHI and the Animal Ethics Committee of Servier Research Institute (IdRS). Compound 2 (25 mg / kg) or its vehicle was intravenously injected weekly for six weeks. Compound 2 was dissolved in 20% (2-hydroxypropyl) -β-cyclodextrin and 25 mM hydrochloric acid. Docetaxel (10 mg / kg intraperitoneally) or its vehicle (Oakes et al.,Proceedings of the National Academy of Sciences of the USA 2012, 109, 2766-71) and injected intraperitoneally weekly one day before Compound 2. Mice were monitored for tumor development three times a week and tumor size was measured using electronic vernier calipers. By measuring the minimum and maximum tumor diameter using the formula: (minimum diameter)2 (Maximum diameter) / 2 to estimate tumor volume. As soon as the tumor appeared, mice were randomized into treatment groups. When tumor volume reaches 80 to 120 mm3 Processing will start. Study Director software (v 3.0, studylog) was used to manage randomization and tumor measurement. The tumor volume exceeds 600 mm3 Mice were sacrificed when the first measurement or appearance was not due to deterioration of animal health due to disease progression or drug toxicity (mice were examined). result Compound 2 alone was not sufficient to inhibit tumor growth. However, in the three PDX models, we observed that compared with docetaxel administered as a single agent, the combination with docetaxel has excellent activity, causing a significant increase in animal survival (Figure 8). These results indicate that MCL-1 inhibitors in combination with taxane compounds may significantly improve tumor response and clinical outcomes.Examples 5 : Combination with Dorset MCL - 1 Inhibitors are well tolerated in vivo NOD SCID IL2 γ receptor knockout mice were treated with docetaxel (15 mg / kg once intraperitoneally) and 25 mg / kg or 50 mg / kg of compound 2 (3 mice per group, intravenously injected , Once a week for 3 weeks). Monitor her weight three times a week for 3 weeks. Compound 2 in combination with docetaxel was well tolerated and did not cause significant weight loss (Figure 9).Examples 6 : Compounds combined with paclitaxel 1 In nude rats MDA - MB - 231 Efficacy in a milk xenograft model method This study evaluated the antitumor activity and tolerability of compound 1 combined with paclitaxel in a female NTac: NIH-Whn nude rat (Taconic) triple negative breast cancer (TNBC) model MDA-MB-231. Compound 1 (free base) and paclitaxel (Sandoz) were used in these studies. Dilute paclitaxel to 1.5 mg / ml with a sterile 5% (w / v) glucose solution according to the manufacturer's instructions for administration at a dose volume of 5 ml / kg at 7.5 mg / kg [in 5% (w / v) The final EL concentrations of ethanol and cetyl alcohol in glucose solution were 10% and 15%, respectively]. Compound 1 was formulated in a lipid formulation (Novartis) at 5 mg / ml for administration at a dose volume of 10 ml / kg at a dose of 50 mg / kg. Triple negative breast cancer cell line MDA-MB-231 was obtained from the ATCC cell bank. 5% CO in air at 37 ° C2 In the atmosphere, DMEM high glucose medium (BioConcept) supplemented with 10% FCS (BioConcept Ltd. Amimed, # 2-01F36-I) and 4 mML-glutamic acid (BioConcept Ltd. Amimed, # 5-10K00-H) Ltd. Amimed). To establish MDA-MB-231, xenograft cells were collected and resuspended in HBSS (Gibco, # 14175) and isoflurane anesthetized animals were injected subcutaneously in the right abdomen with 1 × 107 200 μL of the cells were previously mixed with Matrigel (BD Bioscience, # 354234) (1: 1 v / v). Twenty-four hours before cell seeding, all animals were irradiated with 5Gy for more than 2 minutes using a gamma irradiator. Tumor growth was monitored regularly after cell inoculation, and animals were randomized into treatment groups (n = 7 to 8) with an average tumor volume of approximately 400 mm3 . Each group was treated with the following: 1) intravenous injection of Pacific Paclitaxel and lipid vehicle intravenously; or 2) 7.5 mg / kg intravenous bolus of Pacific Paclitaxel and lipid vehicle intravenously; or 3) used for Formulate the vehicle with paclitaxel intravenously plus 50 mg / kg of Compound 1 intravenously; or 4) 7.5 mg / kg of intravenous paclitaxel plus 50 mg / kg of Compound 1 intravenously. A vehicle for paclitaxel or paclitaxel is administered as a slow bolus dose of 0.5 hours or 16 hours via the tail vein once a week (QW), after which the vehicle of compound 1 in the lipid formulation or compound 1 itself It was administered by intravenous infusion into the tail vein for 15 minutes. For bolus administration and 15-minute infusion, isoflurane / O for animals2 Anesthetize for about 5 and 25 minutes. Tumor volume was measured using calipers 2 to 3 times a week. By (L × W2 × π / 6) Calculated in mm3 Tumor size in units, where W = tumor width and L = tumor length. Animals were also weighed 2 to 3 times a week and frequently tested for any obvious signs of adverse effects. Tumor and weight change data were statistically analyzed using GraphPad Prism 7.00 (GraphPad Software). If the change in the data is a normal distribution, the data is analyzed using one-way ANOVA by post hoc Dunnett test for comparison between the treatment group and the control group. Post hoc Tukey's test was used for comparison within groups. Otherwise, use Kruskal-Wallis grading to test Dunnet after the fact. Where appropriate, results are presented as mean ± SEM. As a measure of efficacy, the T / C% value was calculated at the end of the experiment according to the following formula: (Δ tumor volumedeal with / Δ tumor volumeContrast ) * 100 Tumor regression is calculated according to the following formula:-(Δ tumor volumedeal with / Tumor volumeProcessing begins ) * 100 where Δ tumor volume represents the average tumor volume on the evaluation day minus the average tumor volume at the start of the experiment. Results: efficacy and tolerance Compound 1 was administered at 50 mg / kg after a vehicle of paclitaxel [ethanol: cetyl alcohol polyoxyethylene ether EL: 5% (w / v) glucose (10%: 15%: 75%)] for 0.5 hours or 16 hours is well tolerated. After QW × 7 intravenous infusion, Compound 1 (50 mg / kg QW) in the lipid formulation did not show efficacy in the MDA-MB-231 xenograft model (Figures 10 and 12). Paclitaxel 7.5 mg / kg caused delayed tumor growth (T / C% = 34%) and was significantly different from the vehicle-treated group (p <0.05) (Figure 10 and Figure 12). The combination of 7.5 mg / kg intravenous paclitaxel plus 50 mg / kg intravenous compound 1 administered 0.5 hour or 16 hours apart was surviving on day 28 of treatment (3/8 in both groups) Medium caused 82% and 59% regression, respectively (Figure 10). On the 46th day of the start of treatment, tumor regression in surviving animals 2/8 and 3/8 was 92% and 81%, respectively. On days 28 and 46, tumor volumes in animals from these two combination groups were significantly different (p <0.05) from tumor volumes in animals treated with paclitaxel or Compound 1 alone (Figure 10). The combination of 7.5 mg / kg intravenous paclitaxel plus 25 mg / kg intravenous compound 1 administered 16 hours apart caused tumor arrest in surviving (7/7) animals (15% subsided on day 28 after initiation of treatment and the On day 49, the T / C% value was 2%) (Figure 12). This dosage regimen is well tolerated based on weight changes and clinical signs. The combination of 3.75 mg / kg intravenous paclitaxel plus 50 mg / kg of intravenous compound 1 administered 16 hours apart caused tumor stasis in surviving (7/7) animals to day 35 (on day 28 after treatment 3 % Subsides and T / C% value is 20% on day 49) (Figure 12). This dosage regimen is well tolerated based on weight changes and clinical signs (Figures 11 and 13). These data indicate that the combination of paclitaxel and compound 1 has a significantly positive effect on antitumor activity compared to any of the agents alone.Examples 7 : In vivo MCL - 1 Inhibit PDX Tumors are sensitive to taxane treatment We measured the in vivo therapeutic effect of Compound 1 in combination therapy in the TNBC 110T PDX model. Materials and methods Human breast cancer tissues were obtained from consenting patients through the Royal Melbourne Hospital Tissue Bank, Victorian Cancer Biobank, and Georges-Francois Leclerc Center with the approval of relevant institutional review boards. Human ethics approval was obtained from the Human Research Ethics Committee of the Walter and Eliza Hall College (WEHI) and the Georges-Francois Leclerc Center Human Research Ethics Committee. Breed and maintain NOD SCID IL2 gamma receptor knockout mice or SCID mice according to institutional guidelines. All animal experiments were approved by the Animal Ethics Committee of WEHI and Schweizer Research Institute (IdRS). A group of 40 female NSG mice were inoculated with a thawed single cell suspension of an early passage human breast tumor (TNBC PDX110). Briefly, 100,000 cells were resuspended in 10 µl transplantation buffer (50% fetal bovine serum, 10% 0.04% trypan blue solution and 40% PBS) in a 3: 1 ratio with growth factor-reducing matrigel [ BD] and injected to 3 or 4 weeks of age NOD-SCID-IL2Rγc -/- Female mice were removed from the mammary fat pad. Mice were monitored for tumor development three times a week and tumor size was measured using electronic vernier calipers. By measuring the minimum and maximum tumor diameter using the formula: (minimum diameter)2 (Maximum diameter) / 2 to estimate tumor volume. Once the tumor reaches 60 to 110 mm3 The mice were randomized into treatment groups and the treatment was started. Docetaxel or its vehicle was prepared by dissolving a stock solution (20 mg / ml) with PBS and intraperitoneal injection every 21 days continued for two treatment cycles. The duration of the therapy is indicated by a bar. Compound 1 was dissolved in 20% (2-hydroxypropyl)-β - Cyclodextrin and 25 mM hydrochloric acid. Compound 1 (15 mg / kg) or its vehicle was injected intravenously twice a week for six weeks. The tumor volume exceeds 600 mm3 Mice were sacrificed at the first measurement or worsening of animal health (examination event) due to reasons other than disease progression or drug toxicity. N = 9 to 10 mice per treatment group. result Compound 1 alone was not sufficient to inhibit tumor growth. However, in the PDX model, we observed that compared with docetaxel administered as a single agent, the combination with docetaxel has excellent activity, causing a significant increase in animal survival (Figure 14). These results indicate that MCL-1 inhibitors in combination with taxane compounds may significantly improve tumor response and clinical outcomes.Examples 8 : Derived from carrying patients TNBC Female model SCID Docetaxel and compounds in mice 1 Antitumor activity This study evaluated the antitumor activity of compound 1 combined with docetaxel in a female TNID mouse in the TNBC PDX model OD-BRE-00589. method Docetaxel was formulated at 0.67 mg / ml in 5% ethanol, 5% PS80 and 90% glucose for 10 mg / kg administration. Compound 1 was formulated at 7.5 mg / ml in a lipid formulation (Novartis) for 70 mg / kg administration. OD-BRE-00589 is a triple negative breast cancer PDX, obtained from the IMODI Alliance. Consent patients were obtained from the Georges-Francois Leclerc Center Human Research Ethics Committee. It was transplanted on SCID mice as 27 mm3 Fragment of volume. Periodically monitor tumor growth after fragment transplantation and randomize animals to an average tumor volume of approximately 200 mm on day 11 after transplantation3 Treatment group (n = 8). The control group was left untreated and the other group was treated with the following: 1) 70 mg / kg compound 1 intravenously, or 2) 10 mg / kg docetaxel intravenously, or 3) 10 mg / kg docetaxel intravenously Within 30 minutes, 70 mg / kg of Compound 1 was followed, or 4) 10 mg / kg of docetaxel was administered intravenously, followed by 70 mg / kg of Compound 1 72 hours later. One dose was administered in the tail vein. Tumor volume was measured using calipers 2 to 3 times a week. Tumor volume use formula: length × width2 / 2 calculation. Animals were also weighed 2 to 3 times a week and frequently tested for any obvious signs of adverse effects. result Compound 1 alone was not sufficient to inhibit tumor growth. However, in the PDX model, we observed that compared with docetaxel administered as a single agent, the combination with docetaxel has excellent activity, causing a significant increase in antitumor activity (Figure 15). These results indicate that MCL-1 inhibitors in combination with taxane compounds may significantly improve tumor response and clinical outcomes.Examples 9 : In resistance to docetaxel PDX model Compound in combination with paclitaxel 1 Efficacy study method Tests have confirmed a PDX model that is resistant to docetaxel in vivo. Each treatment group included 5 female Swiss nude mice, aged 6 to 8 weeks of age. When xenografts reach an average tumor volume of about 120 to 150 mm3 Processing will start. Subsequent groups of mice were randomly affected by different treatments. The number of transplanted animals depends on the homogeneity of tumor growth. Formulated in a lipid formulation, Compound 1 was administered intravenously at 70 mg / kg once a week. The formulation must be prepared temporarily. Paclitaxel diluted in 0.9% NaCl was administered intraperitoneally at 25 mg / kg. Paclitaxel QW was administered for 16 hours before Compound 1 was administered. Dosing regimens for different treatments are defined as follows: Tumor size was measured twice a week and the weight of individual mice was measured once a week. Until the median tumor volume of most response groups began to grow again, the treatment was completed. The time it took for mice to relapse was compared between groups after treatment was discontinued. Using Statview software, compare tumor volume and / or relative tumor volume (RTV, ratio of volume divided by initial volume at day 1 times 100), optimized growth inhibition (RTV Ratio (× 100)) divided by RTV in control), growth delay (200 mm in treatment group and control group)3 The number of days necessary to expand the initial tumor volume by 4 times) and changes in body weight. If recurrence is observed after paclitaxel treatment, the tumor is again challenged with the compound 1 + paclitaxel combination. This was done by including 10 mice in the paclitaxel-treated group and subsequently treating tumor recurring mice (5 animals) with paclitaxel alone or treating tumor recurring mice (5 animals) in combination , Or by using non-randomized mice from efficacy studies. If an initial response to paclitaxel is observed, additional animals remaining after randomization are used for this study. result Compound 1 alone was not sufficient to inhibit tumor growth. However, we have observed that compared with the administration of paclitaxel as a single agent, it has excellent activity in combination with paclitaxel, causing a significant increase in antitumor activity in a PDX model resistant to taxane compounds. These results indicate that MCL-1 inhibitors in combination with taxane compounds may significantly improve tumor response and clinical outcomes.

圖 1 繪示在代表性MDA-MB-453乳癌細胞株中與化合物1組合之太平洋紫杉醇之抑制、洛伊(Loewe)過量抑制及生長抑制之矩陣。圖 2 繪示在代表性MDA-MB-468乳癌細胞株中與化合物1組合之太平洋紫杉醇之抑制、洛伊過量抑制及生長抑制之矩陣。圖 3 繪示在代表性H522肺癌細胞株中與化合物1組合之太平洋紫杉醇之抑制、洛伊過量抑制及生長抑制之矩陣。圖 4 繪示在兩個獨立實驗中在乳癌細胞株MDA-MB-453中藉由化合物2組合太平洋紫杉醇得到之細胞生長抑制(左)及洛伊過量抑制(右)之例示性細胞生長抑制作用及協同組合矩陣。作用矩陣之值在0 (不抑制)至100 (完全抑制)範圍內。協同矩陣之值表示生長抑制超過基於所測試濃度之化合物2及太平洋紫杉醇之單一藥劑活性所計算的理論相加作用的程度。圖 5 繪示在兩個獨立實驗中在肺癌細胞株H522中藉由化合物2組合太平洋紫杉醇得到之細胞生長抑制(左)及洛伊過量抑制(右)之例示性細胞生長抑制作用及協同組合矩陣。作用矩陣之值在0 (不抑制)至100 (完全抑制)範圍內。協同矩陣之值表示生長抑制超過基於所測試濃度之化合物2及太平洋紫杉醇之單一藥劑活性所計算的理論相加作用的程度。圖 6 繪示化合物2與多西他賽之協同作用。在使用碘化丙錠(PI)染色進行活力分析之前72小時，將SK-BR-3細胞在化合物2 (30 nM)存在下，用多西他賽(2 nM)處理或不進行處理，使用或不使用QVD (10 μM)。結果作為未經處理細胞之百分比展示且代表3至5個獨立實驗。圖 7 繪示化合物2與多西他賽之協同作用。將SK-BR-3細胞用增大濃度之化合物2及多西他賽處理72小時，隨後在BLISS得分分析之後使用細胞滴定Glo進行活力分析。在豎直軸線上BLISS協同值＞0.0。圖 8 繪示在TNBC PDX模型中化合物2與多西他賽提高動物存活率之功效。用媒劑單獨(黑色線)、多西他賽(在第0天及第21天10 mg/kg腹膜內)加化合物2之媒劑(深灰色線)、化合物2 (每週一次25 mg/kg靜脈內持續6週)加多西他賽之媒劑(淺灰色線)或經組合之多西他賽與化合物2 (虛線)處理之攜帶110T (每組n=10至12隻小鼠)、838T (每組n=12隻小鼠)或PDX OD-BRE-0589 (每組8隻小鼠)之小鼠之卡本-麥爾(Kaplan-Meier)存活率曲線。右圖：個別腫瘤體積曲線。由於獨立於療法之外的年齡相關疾病，在第120天終結PDX 838T模型。顯示組合療法對比多西他賽單獨之對數秩(Mantel-Cox) p值。圖 9 繪示在療法期間正常體重之保持。將NOD SCID IL2 γ受體基因剔除小鼠用多西他賽(15 mg/kg，一次腹膜內)及25 mg/kg或50 mg/kg之化合物2 (每組3隻小鼠，靜脈內注射，每週一次持續3週)處理。每週三次監測其體重持續3週。作為單一藥劑之化合物2療法或與多西他賽組合之化合物2療法具有良好耐受性。圖 10 繪示在攜帶MDA-MB-231異種移植物之雌性裸大鼠(一種TNBC模型)中，太平洋紫杉醇及化合物1 (在圖中命名為化合物A) 單獨及組合時之功效。在雌性裸大鼠中，藉由皮下接種人類TNBC MDA-MB-231細胞(1×107 個細胞/200 µL HBSS/基質膠(Matrigel)1:1 v/v)來形成腫瘤。將具有適當尺寸腫瘤之動物隨機分組(n=7至8)，每組平均腫瘤體積約400 mm3 。根據(L×W2 ×π/6)，使用兩個最大直徑估算腫瘤體積，且每週量測體重2至3次。數據以平均值±SEM或個別腫瘤體積表示。*係相比於媒劑組，p＜0.05 (藉由事後鄧尼特測試(post hoc Dunnett's test)之單因素變異數分析(ANOVA))。圖 11 繪示在攜帶MDA-MB-231異種移植物之雌性裸大鼠(一種TNBC模型)中，太平洋紫杉醇及化合物1 (在圖中命名為化合物A) 單獨及組合時之耐受性。在雌性裸大鼠中，藉由皮下接種人類TNBC MDA-MB-231細胞(1×107 個細胞/200 µL HBSS/基質膠1:1 v/v)來形成腫瘤。將具有適當尺寸腫瘤之動物隨機分組(n=7至8)，每組平均腫瘤體積約400 mm3 。根據(L×W2 ×π/6)，使用兩個最大直徑估算腫瘤體積，每週量測體重2至3次。圖 12 繪示在攜帶MDA-MB-231異種移植物之雌性裸大鼠(一種TNBC模型)中，太平洋紫杉醇及化合物1 (在圖中命名為化合物A)單獨及依不同劑量組合療程之功效。在雌性裸大鼠中，藉由皮下接種人類TNBC MDA-MB-231細胞(1×107 個細胞/200 µL HBSS/基質膠1:1 v/v)來形成腫瘤。將具有適當尺寸腫瘤之動物隨機分組(n=7至8)，每組平均腫瘤體積約400 mm3 。根據(L×W2 ×π/6)，使用兩個最大直徑估算腫瘤體積，每週量測體重2至3次。數據以平均值±SEM或個別腫瘤體積表示。*係相比於媒劑組，p＜0.05 (藉由事後鄧尼特測試之單因素變異數分析)。圖 13 繪示在攜帶MDA-MB-231異種移植物之雌性裸大鼠(一種TNBC模型)中，太平洋紫杉醇及化合物1 (在圖中命名為化合物A) 單獨及依不同劑量組合療程之耐受性。在雌性裸大鼠中藉由皮下接種人類TNBC MDA-MB-231細胞(1×107 個細胞/200 µL HBSS/基質膠1:1 v/v)來形成腫瘤。將具有適當尺寸腫瘤之動物隨機分組(n=7至8)，每組平均腫瘤體積約400 mm3 。根據(L×W2 ×π/6)，使用兩個最大直徑估算腫瘤體積，每週量測體重2至3次。圖 14 繪示化合物1與多西他賽之協同作用。圖 15 繪示在攜帶患者衍生TNBC模型之雌性SCID小鼠中單獨及以組合形式靜脈內投與之多西他賽及化合物1之抗腫瘤活性。首先投與多西他賽，接著30分鐘或72小時後投與化合物1。 Figure 1 shows a matrix of paclitaxel inhibition, Loewe excess inhibition, and growth inhibition in combination with Compound 1 in a representative MDA-MB-453 breast cancer cell line. FIG. 2 shows a matrix of paclitaxel inhibition, Loe excess inhibition, and growth inhibition in combination with Compound 1 in a representative MDA-MB-468 breast cancer cell line. FIG. 3 shows a matrix of paclitaxel inhibition, Loe excess inhibition, and growth inhibition in combination with Compound 1 in a representative H522 lung cancer cell line. Figure 4 illustrates exemplary cell growth inhibition (left) and Roy overdose inhibition (right) of breast cancer cell line MDA-MB-453 by compound 2 in combination with paclitaxel in two independent experiments. And cooperative combination matrix. The value of the action matrix is in the range of 0 (not inhibited) to 100 (fully inhibited). The values of the synergy matrix represent the extent to which growth inhibition exceeds the theoretical additive effect calculated based on the single agent activity of the tested concentration of Compound 2 and paclitaxel. Figure 5 shows exemplary cytostatic and synergistic combination matrices of cytostatic (left) and Loy excess inhibition (right) obtained by compound 2 combined with paclitaxel in lung cancer cell line H522 in two independent experiments . The value of the action matrix is in the range of 0 (not inhibited) to 100 (fully inhibited). The values of the synergy matrix represent the extent to which growth inhibition exceeds the theoretical additive effect calculated based on the single agent activity of the tested concentration of Compound 2 and paclitaxel. Figure 6 illustrates the synergy between compound 2 and docetaxel. 72 hours prior to viability analysis using propidium iodide (PI) staining, SK-BR-3 cells were treated with or without docetaxel (2 nM) in the presence of compound 2 (30 nM), used Or do not use QVD (10 μM). Results are shown as a percentage of untreated cells and represent 3 to 5 independent experiments. Figure 7 illustrates the synergy between compound 2 and docetaxel. SK-BR-3 cells were treated with increasing concentration of Compound 2 and docetaxel for 72 hours, followed by cell titration Glo for viability analysis after BLISS score analysis. The BLISS coordination value is greater than 0.0 on the vertical axis. Figure 8 illustrates the efficacy of compound 2 and docetaxel in improving the survival rate of animals in the TNBC PDX model. Vehicle alone (black line), docetaxel (10 mg / kg intraperitoneally on days 0 and 21) plus vehicle 2 (dark gray line) and compound 2 (25 mg / weekly) kg intravenously for 6 weeks) plus docetaxel vehicle (light gray line) or combined docetaxel and compound 2 (dotted line) carrying 110T (n = 10 to 12 mice per group) Kaplan-Meier survival curve for mice of 838T (n = 12 mice per group) or PDX OD-BRE-0589 (8 mice per group). Right: Individual tumor volume curve. Due to age-related diseases independent of therapy, the PDX 838T model was terminated on day 120. Mantel-Cox p-value for combination therapy versus docetaxel alone. Figure 9 illustrates the maintenance of normal body weight during therapy. NOD SCID IL2 γ receptor knockout mice were treated with docetaxel (15 mg / kg, once intraperitoneally) and 25 mg / kg or 50 mg / kg of compound 2 (3 mice per group, injected intravenously) , Once a week for 3 weeks). Monitor her weight three times a week for 3 weeks. Compound 2 therapy as a single agent or Compound 2 therapy in combination with docetaxel is well tolerated. Figure 10 shows the efficacy of paclitaxel and compound 1 (named compound A in the figure) alone and in combination in a nude female rat (a TNBC model) carrying an MDA-MB-231 xenograft. In female nude rats, tumors were formed by subcutaneously inoculating human TNBC MDA-MB-231 cells (1 × 10 7 cells / 200 µL HBSS / Matrigel 1: 1 v / v). Animals with tumors of appropriate size were randomly grouped (n = 7 to 8), with an average tumor volume of approximately 400 mm 3 in each group. According to (L × W 2 × π / 6), the tumor volume was estimated using the two largest diameters, and body weight was measured 2 to 3 times a week. Data are expressed as mean ± SEM or individual tumor volume. * P <0.05 compared to vehicle group (by one-way analysis of variance (ANOVA) with post hoc Dunnett's test). Figure 11 shows the tolerance of paclitaxel and compound 1 (named compound A in the figure) alone and in combination in a nude female rat (a TNBC model) carrying an MDA-MB-231 xenograft. In female nude rats, tumors were formed by subcutaneously inoculating human TNBC MDA-MB-231 cells (1 × 10 7 cells / 200 µL HBSS / Matrix 1: 1 v / v). Animals with tumors of appropriate size were randomly grouped (n = 7 to 8), with an average tumor volume of approximately 400 mm 3 in each group. According to (L × W 2 × π / 6), the tumor volume was estimated using the two largest diameters, and the body weight was measured 2 to 3 times a week. Figure 12 shows the efficacy of paclitaxel and Compound 1 (named Compound A in the figure) alone and in combination with different doses in female nude rats (a TNBC model) carrying MDA-MB-231 xenografts. In female nude rats, tumors were formed by subcutaneously inoculating human TNBC MDA-MB-231 cells (1 × 10 7 cells / 200 µL HBSS / Matrix 1: 1 v / v). Animals with tumors of appropriate size were randomly grouped (n = 7 to 8), with an average tumor volume of approximately 400 mm 3 in each group. According to (L × W 2 × π / 6), the tumor volume was estimated using the two largest diameters, and the body weight was measured 2 to 3 times a week. Data are expressed as mean ± SEM or individual tumor volume. * P <0.05 compared to vehicle group (by single factor analysis of post hoc Dunnett test). Figure 13 shows the tolerance of paclitaxel and compound 1 (named compound A in the figure) alone and in combination with different doses in female nude rats (a TNBC model) carrying MDA-MB-231 xenografts. Sex. Tumors were formed in female nude rats by subcutaneously inoculating human TNBC MDA-MB-231 cells (1 × 10 7 cells / 200 µL HBSS / Matrix 1: 1 v / v). Animals with tumors of appropriate size were randomly grouped (n = 7 to 8), with an average tumor volume of approximately 400 mm 3 in each group. According to (L × W 2 × π / 6), the tumor volume was estimated using the two largest diameters, and the body weight was measured 2 to 3 times a week. Figure 14 illustrates the synergistic effect of Compound 1 with docetaxel. Figure 15 shows the antitumor activity of docetaxel and compound 1 administered intravenously, alone and in combination, in female SCID mice carrying a patient-derived TNBC model. Docetaxel was administered first, followed by Compound 1 30 minutes or 72 hours later.

Claims (21)

一種組合，其包含：(a)MCL-1抑制劑，其係(2R)-2-{[(5S a )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(5-氟呋喃-2-基)噻吩并[2,3-d]嘧啶-4-基]氧基}-3-(2-{[1-(2,2,2-三氟乙基)-1H-吡唑-5-基]甲氧基}苯基)丙酸，或(2R)-2-{[(5S a )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸，及(b)紫杉烷化合物，其係太平洋紫杉醇(paclitaxel)或多西他賽(docetaxel)，用於同時、依序或分開使用。A combination comprising: (a) MCL-1 inhibitor, which is (2 R ) -2-{[(5 S a ) -5- {3-chloro-2-methyl-4- [2- ( 4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl) thieno [2,3- d ] pyrimidin-4-yl] oxy}- 3- (2-{[1- (2,2,2-trifluoroethyl) -1 H -pyrazol-5-yl] methoxy} phenyl) propionic acid, or (2 R ) -2- {[(5 S a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4- Fluorophenyl) thieno [2,3- d ] pyrimidin-4-yl] oxy} -3- (2-{[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy } Phenyl) propionic acid, and (b) taxane compounds, which are paclitaxel or docetaxel, for simultaneous, sequential or separate use. 如請求項1之組合，其中在組合治療期間該(2R)-2-{[(5S a )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸之劑量為25mg至1500mg。As in the combination of claim 1, where (2 R ) -2-{[(5 S a ) -5- {3-chloro-2-methyl-4- [2- (4-methyl Piperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3- d ] pyrimidin-4-yl] oxy} -3- (2-{[ The dosage of 2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propionic acid is 25 mg to 1500 mg. 如請求項1之組合，其中在組合治療期間該(2R)-2-{[(5S a )-5-{3-氯-2-甲基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸係一週投與一次。As in the combination of claim 1, where (2 R ) -2-{[(5 S a ) -5- {3-chloro-2-methyl-4- [2- (4-methyl Piperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3- d ] pyrimidin-4-yl] oxy} -3- (2-{[ 2- (2-Methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propionic acid is administered once a week. 如請求項1之組合，其中該MCL-1抑制劑及該紫杉烷化合物經靜脈內投與。The combination of claim 1, wherein the MCL-1 inhibitor and the taxane compound are administered intravenously. 如請求項1之組合，其中該MCL-1抑制劑經口投與且該紫杉烷化合物經靜脈內投與。The combination of claim 1, wherein the MCL-1 inhibitor is administered orally and the taxane compound is administered intravenously. 如請求項1之組合，其用於治療癌症。As in the combination of claim 1, it is used to treat cancer. 如請求項6所使用之組合，其中該MCL-1抑制劑及該紫杉烷化合物所提供之量為治療癌症之共同治療有效量。The combination as used in claim 6, wherein the amount provided by the MCL-1 inhibitor and the taxane compound is a jointly therapeutically effective amount for treating cancer. 如請求項6所使用之組合，其中該MCL-1抑制劑及該紫杉烷化合物所提供之量為治療癌症之協同有效量。The combination as used in claim 6, wherein the amount provided by the MCL-1 inhibitor and the taxane compound is a synergistically effective amount for treating cancer. 如請求項6所使用之組合，其中該MCL-1抑制劑及該紫杉烷化合物以協同有效量提供，其能夠減少癌症治療中各化合物之所需劑量，同時提供有效的癌症治療，且最終減少副作用。The combination as used in claim 6, wherein the MCL-1 inhibitor and the taxane compound are provided in a synergistically effective amount, which can reduce the required dose of each compound in cancer treatment while providing effective cancer treatment, and ultimately Reduce side effects. 如請求項6所使用之組合，其中該癌症為乳癌。The combination as used in claim 6, wherein the cancer is breast cancer. 如請求項6所使用之組合，其中該癌症為肺癌。The combination as used in claim 6, wherein the cancer is lung cancer. 如請求項1之組合，其另外包含一或多種賦形劑。If the combination of claim 1, it additionally contains one or more excipients. 一種醫藥組合物，其包含如請求項1至5中任一項之組合，再與一或多種醫藥學上可接受之賦形劑組合。A pharmaceutical composition comprising the combination of any one of claims 1 to 5 in combination with one or more pharmaceutically acceptable excipients. 如請求項13之醫藥組合物，其用於治療癌症。The pharmaceutical composition according to claim 13, which is used for treating cancer. 如請求項14之醫藥組合物，其中該癌症為乳癌。The pharmaceutical composition according to claim 14, wherein the cancer is breast cancer. 如請求項14之醫藥組合物，其中該癌症為肺癌。The pharmaceutical composition according to claim 14, wherein the cancer is lung cancer. 一種如請求項1組合之用途，其用於製造治療癌症之藥物。A use as claimed in claim 1, which is used to manufacture a medicine for treating cancer. 如請求項17組合之用途，其中該癌症為乳癌。The use as claimed in claim 17, wherein the cancer is breast cancer. 如請求項17組合之用途，其中該癌症為肺癌。The use as claimed in claim 17, wherein the cancer is lung cancer. 一種藥物，其分開包含或一起包含：(a)如請求項1所定義之MCL-1抑制劑，及(b)如請求項1所定義之紫杉烷化合物，用於同時、依序或分開投與，且其中該MCL-1抑制劑及該紫杉烷化合物以治療癌症之有效量提供。A medicine separately or together comprising: (a) an MCL-1 inhibitor as defined in claim 1, and (b) a taxane compound as defined in claim 1, for simultaneous, sequential or separate Administered, and wherein the MCL-1 inhibitor and the taxane compound are provided in an effective amount to treat cancer. 一種如請求項1組合之用途，其用於製造用於使(i)難以用至少一種化學療法治療或(ii)用化學療法治療之後復發或(i)及(ii)兩者之患者敏感之藥物。A use as claimed in claim 1, which is used to manufacture a patient for making (i) difficult to treat with at least one chemotherapy or (ii) relapse after treatment with chemotherapy or (i) and (ii) drug.
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